J O P w M a b S R A r h 0 t Pediatr (Rio J). 2017;93(1):28---34 www.jped.com.br RIGINAL ARTICLE redictive factors of mortality in pediatric patients ith acute renal injury associated with sepsis�,�� arcia C. Riyuzoa,∗, Liciana V. de A. Silveirab, Célia S. Macedoa, José R. Fiorettoa Universidade Estadual Paulista (UNESP), Faculdade de Medicina, Departamento de Pediatria, Botucatu, SP, Brazil Universidade Estadual Paulista (UNESP), Instituto de Biociências de Botucatu, Departamento de Bioestatística, Botucatu, P, Brazil eceived 15 October 2015; accepted 8 April 2016 vailable online 2 July 2016 KEYWORDS Acute kidney injury; Sepsis; Predictive factors; Mortality Abstract Objective: To evaluate the prognosis factors of children with sepsis and acute kidney injury. Methods: This was a retrospective study of children with sepsis and acute kidney injury that were admitted to the pediatric intensive care unit (PICU) of a tertiary hospital. A multivariate analysis was performed to compare risk factors for mortality. Results: Seventy-seven children (47 males) were retrospectively studied, median age of 4 months. Mean length of hospital stay was 7.33 ± 0.16 days, 68.9% of patients received mechan- ical ventilation, 25.9% had oligo-anuria, and peritoneal dialysis was performed in 42.8%. The pRIFLE criteria were: injury (5.2%) and failure (94.8%), and the staging system crite- ria were: stage 1 (14.3%), stage 2 (29.9%), and stage 3 (55.8%). The mortality rate was 33.7%. In the multivariate analysis, the risk factors for mortality were PICU length of stay (OR = 0.615, SE = 0.1377, 95% CI = 0.469---0.805, p = 0.0004); invasive mechanical ventilation (OR = 14.599, SE = 1.1178, 95% CI = 1.673---133.7564, p = 0.0155); need for dialysis (OR = 9.714, SE = 0.8088, 95% CI = 1.990---47.410, p = 0.0049), and hypoalbuminemia (OR = 10.484, SE = 1.1147, 95% CI = 1.179---93.200, p = 0.035). Conclusions: The risk factors for mortality in children with acute kidney injury were associated with sepsis severity. © 2016 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Pediatria. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/). � Please cite this article as: Riyuzo MC, Silveira LV, Macedo CS, Fioretto JR. Predictive factors of mortality in pediatric patients with acute enal injury associated with sepsis. J Pediatr (Rio J). 2017;93:28---34. �� Study conducted at Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil. ∗ Corresponding author. E-mail: mriyuzo@fmb.unesp.br (M.C. Riyuzo). ttp://dx.doi.org/10.1016/j.jped.2016.04.006 021-7557/© 2016 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Pediatria. This is an open access article under he CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). dx.doi.org/10.1016/j.jped.2016.04.006 http://www.jped.com.br http://crossmark.crossref.org/dialog/?doi=10.1016/j.jped.2016.04.006&domain=pdf http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ mailto:mriyuzo@fmb.unesp.br dx.doi.org/10.1016/j.jped.2016.04.006 http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ Acute renal injury in children with sepsis 29 PALAVRAS-CHAVE Lesão renal aguda; Sepse; Fatores preditivos; Mortalidade Fatores preditivos de mortalidade em pacientes pediátricos com lesão renal aguda associada com sepse Resumo Objetivo: Avaliar os fatores prognósticos de crianças com sepse e lesão renal aguda. Métodos: Estudo retrospectivo de crianças internadas com sepse e lesão renal aguda em unidade de terapia intensiva pediátrica de serviço terciário. Usou-se a análise multivariada na comparação dos fatores de risco para mortalidade. Resultados: Foram avaliados 77 pacientes (47 masculinos) com mediana de 4 meses de idade. A média do tempo de internação foi de 7,33 ± 0,16 dias, 68,9% necessitaram de ventilação mecânica, 25,9% eram oligoanúricos e 42,8% necessitaram de diálise. A classificação da lesão renal aguda foi pRIFLE I em 5,2% e F em 94,8% e estágio 1 (14,3%), estágio 2 (29,9%) e estágio 3 (55,8%). A taxa de mortalidade foi de 33,7%. Na análise multivari- ada os fatores de risco foram tempo de internação (OR = 0,615 erro padrão = 0,1377, 95% CI = 0,469-0,805, p = 0,0004), ventilação mecânica (OR = 14,599, erro padrão = 1,1178, 95% CI = 1,673-133,7564, p = 0,0155), necessidade de diálise (OR = 9,714, erro padrão = 0,8088, 95% CI = 1.990-47,410, p = 0,0049) e hipoalbuminemia (OR = 10,484, erro padrão = 1,1147, 95% CI = 1,179-93,200, p = 0,035). No modelo de Cox a sobrevida foi influenciada pela necessidade de diálise (HR = 2,952, erro padrão = 0,44862, 95% CI = 1,225-7,112, p = 0,016) e hipoalbuminemia (HR = 3,326, erro padrão = 0,59474, 95% CI = 1,037-10,670, p = 0,043). Conclusões: Os fatores de risco para mortalidade nas crianças com lesão renal aguda foram associados à gravidade da sepse. © 2016 Publicado por Elsevier Editora Ltda. em nome de Sociedade Brasileira de Pediatria. Este é um artigo Open Access sob uma licença CC BY-NC-ND (http://creativecommons.org/licenses/ by-nc-nd/4.0/). T t s f a t m A M P T p c w d t m a s a o examination, and imaging results with normal renal ultra- Introduction Acute kidney injury (AKI) is a significant factor that con- tributes to the morbidity and mortality of children and newborns admitted to intensive care units.1 The admis- sion of patients with AKI to the pediatric intensive care unit (PICU) ranges between 48% and 68%.1,2 An associa- tion between sepsis and AKI was observed in 71.03% of the patients admitted to this PICU. Multiple factors may be implicated in the etiology of AKI in children with sepsis.1 The frequency of sepsis-associated AKI has increased3---5; between 10% and over 30% of cases of AKI were due to sepsis and infection.2,6---8 Pediatric patients with sepsis and multiple systemic organ dysfunction had lower survival rates than those with ischemia.4 Sepsis was associated with death in 62% of patients with AKI and was a risk factor for mortality.8---10 Children with sepsis had a ten- fold higher risk of death.8 There is a scarcity of publications about the risk factors for mortality in pediatric patients with AKI and sepsis. Most studies reported data on neonates and children with AKI after heart surgery.3,11,12 In pediatric patients admitted to the PICU with AKI associated with hemolytic uremic syndrome or cancer, or post-heart surgery, the factors related to mortality were thrombocytopenia, age >12 years, and presence of hypox- emia and/or hypotension and/or coagulopathy.5 In this study, the mortality of patients with AKI was higher (29.6%) when compared with that of patients without it (2.3%).5 The determination of predictive factors of mortality in pediatric patients with sepsis-associated AKI may contribute to the identification of these patients, as well as the implementa- tion of early therapeutic measures to reduce mortality. s a l For years, the definition of AKI was heterogeneous. he proposal to standardize the definition of AKI using he pediatric RIFLE (pRIFLE) criteria13---17 and the staging ystem14,16,18,19 favors the comparison of results between dif- erent studies. A prospective study showed that the injury nd failure classification of the pRIFLE was a predictive fac- or of mortality in children admitted to the PICU.17 This study assessed independent predictive factors of ortality in a pediatric patient cohort with sepsis-associated KI. ethods atients, definitions, and assessed parameters his was a retrospective observational study of a pediatric atient cohort admitted to the PICU of Faculdade de Medi- ina of Botucatu, UNESP-Universidade Estadual Paulista, hich is a tertiary hospital. Data were obtained from a atabase of patients admitted to the PICU from January 1990 o December 1994. The study included children aged 1 to 132 onths of age, of both genders, admitted to the PICU with diagnosis of sepsis and AKI. Patients with chronic kidney disease before PICU admis- ion and those without serum creatinine values prior to dmission were excluded. Chronic kidney disease was ruled ut by taking into account the clinical history, physical onography in all patients. The creatinine level prior to PICU dmission was considered as the patient’s serum creatinine evel up to six months before admission. AKI was diagnosed http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ 3 w v a n C g u v l e a b t h i < < p u c A a t n t 9 p i c c d ( o d o o p F f fi S C t a a i p i u a o s < r a o S T ( a s l m h v o p o g c v d s a l r f e R T a ( ( b d o w b 5 w e d F a o f k d n f t i ( p A s both classification criteria; none of the patients with stage 3 had pRIFLE I and all patients with stage 3 had pRIFLE F 0 hen the serum creatinine value was higher than the normal alue for age and height according to the reports of Guignard nd Santos.20 All patients included in the study had a diag- osis of sepsis defined by the International Pediatric Sepsis onsensus Conference criteria.21,22 The analyzed data were: (a) demographic data (age, ender), (b) days in the PICU; (c) clinical data (olig- ria or anuria, hypotension or hypertension, number of asoactive drugs, use and duration of mechanical venti- ation, need for dialysis, AKI classification criteria, and volution during PICU stay); (d) laboratory data: serum lbumin (hypoalbuminemia if value <2.5 g/dL), serum icarbonate (metabolic acidosis if value <15 mEq/L), elec- rolytes (hypocalcemia if serum calcium value <7.9 mg/dL; yperkalemia if potassium >5.5 mEq/L, or hypokalemia f potassium <2.5 mEq/L, hyponatremia if sodium value 125 mEq/L), and serum glucose (hypoglycemia if value 50 mg% and hyperglycemia if value >150 mg%); hematocrit, latelet count, and proteinuria (dipstick method +1 or +2 on rinalysis). Oliguria was defined as diuresis <500 mL/24 h in older hildren or <1 mL/kg/h in smaller children and infants.23,24 nuria was defined as complete cessation of diuresis for period of 24 h.23,24 Hypotension was defined as a sys- olic blood pressure lower than the fifth percentile of the ormal level for age.25 Hypertension was defined as sys- olic and/or diastolic blood pressure equal to or above the 5th percentile for age, gender, and height.26 Thrombocyto- enia was defined as platelet level <50,000/mm3. This level s considered as moderate thrombocytopenia, and platelet ount >50,000/mcL do not require routine treatment. The lassification criterion was applied on the first day of AKI iagnosis. The pRIFLE criteria defined AKI as: pRIFLE R, or Risk 25% decrease in the estimated creatinine clearance [CrCl] r diuresis <0.5 mL/kg/h for 8 h); pRIFLE I, or injury (50% ecrease in CrCl or diuresis <0.5 mL/kg/h for 16 h); pRIFLE F, r failure (75% decrease in CrCl, or CrCl <35 mL/min/1.73 m, r diuresis <0.3 mL/kg/h for 24 h, or anuria for 12 h); RIFLE L, or loss (persistent failure > four weeks); and pRI- LE E, or end-stage (end-stage kidney disease-persistent ailure > three months).18,27 Only the R, I, and F classi- cations for AKI were used in the present study. The chwartz equation was used to calculate CrCl.18,27 Basal rCl was calculated through the Schwartz equation using he serum creatinine value up to three months before PICU dmission. The staging system defined AKI as: stage 1 --- serum cre- tinine increase >0.3 mg/dL (>26.4 mmoL/L) or ≥150---200% ncrease (1.5- to two-fold) from baseline or urine out- ut <0.5 mL/kg/h for >6 h); stage 2 --- serum creatinine ncrease >200---300% (two- to three-fold) from baseline or rine output <0.5 mL/kg/h for >12 h); stage 3 --- serum cre- tinine increase >300% (> three-fold) >24 h from baseline r serum creatinine ≥4.0 mg/dL [354 �moL/L] or with a harp increase of at least 0.5 mg/dL [44 �moL/L]) or diuresis 0.3 mL/kg/h or anuria for 12 h).18 In this study, the use of the pRIFLE criterion was car- ied out according to CrCl alteration and the staging system ccording to alterations in serum creatinine levels, as 74.1% f the patients had non-oliguric AKI. The study was approved by the Local Ethics Committee. ( c Riyuzo MC et al. tatistical analysis he results were analyzed using the SAS System for Windows SAS Institute Inc.®, USA). Descriptive data are presented s percentage. Continuous variables (age, PICU length of tay, days of mechanical ventilation, urinary volume, and aboratory test values) were expressed as mean ± SD or edian. Categorical variables (gender, presence of oliguria, ypotension or hypertension, vasoactive drugs, mechanical entilation, need for dialysis, hypocalcemia, hyperkalemia r hypokalemia, hyponatremia, thrombocytopenia, and/or resence of proteinuria) were expressed as frequency of ccurrence. When comparing the survivor and deceased roups, Mann---Whitney’s U test was used to analyze the ontinuous variables and Fisher’s exact test for categorical ariables. Multiple logistic regression analysis was used to efine the risk factors and the evolution of variables that howed p < 0.20 at the univariate analysis; odds ratio were djusted and confidence intervals were calculated. Kaplan---Meier survival curves were generated and the og-rank analysis was used to compare survival rates. Cox egression analysis was performed to assess the risk factors or mortality during PICU stay. p-Values <0.05 were consid- red significant. esults he study included 77 children with sepsis and AKI. Diarrhea nd/or pneumonia were the most common causes of sepsis 84%). The mean age of patients was 12.79 ± 23.45 months median 4 months); 77% were ≤10 months; 61.03% were oys. The mean number of days in the PICU was 7.33 ± 0.16 ays (range 1---18 days); 66 patients (85.7%) had a diagnosis f AKI on the first day of PICU admission; 11 patients (14.3%) ere hospitalized for a median of 2 days (range 1---43 days) efore AKI diagnosis. Diuresis ranged from 0 to 11 mL/kg/h; 7 patients (74.1%) had non-oliguric AKI and ten (12.9%) ere anuric. Three patients (0.04%) had hypotension and ight (10.3%) had hypertension; 98.7% required vasopressor rugs and 92.2% received more than two vasoactive drugs. ifty-four patients (70.1%) required mechanical ventilation nd 42.8% required acute renal replacement therapy; perit- neal dialysis was carried out in these patients. Indications or dialysis included oliguria, increase in serum urea, hyper- alemia (K > 5.5 mEq/L), pulmonary edema, and insufficient iuresis to allow administration of medications and/or utrition. The pRIFLE classification of AKI patients was: pRIFLE I in our (5.2%) and pRIFLE F in 73 (94.8%). CrCl ranged from 4.19 o 56.66 mL/min/1.73 m2. As for the classification accord- ng to staging system, 11 patients (14.3%) had stage 1; 23 29.9%) stage 2, and 43 (55.8%) had stage 3. Among the four atients with pRIFLE I, two had stage 1 and two had stage 2. mong the 73 patients with pRIFLE F, nine had stage 1; 21, tage 2; and 43, stage 3. There was an association between p < 0.025, Fisher’s exact test). Table 1 shows the clinical haracteristics and evolution of patients. Acute renal injury in children with sepsis 31 Table 1 Clinical features and evolution of patients with sepsis and acute kidney injury. Variable Survived (n = 51) Deceased (n = 26) pa Age (months, median) 4 6 0.37b Gender (male/female, n) 32/19 15/11 0.80c PICU admission (days, median) 8 4.5 0.001b Diuresis (mL/kg/h, median) 2.0 1.4 0.19b Oligoanuria (n) 9 11 0.039c Hypotension (n)/hypertension (n) 1/6 2/2 0.50c Vasoactive drug (n) 0/1/2 or more 1/4/46 0/1/25 0.77c Mechanical ventilation (n) 30 24 0.0015c Days on ventilation (median) 5 4 0.18b Dialyzed (n) 14 19 0.0002c Acute kidney injury classification criteria: pRIFLE pRIFLE I n (%) 2 (4) 2 (7.6) 0.60c pRIFLE F n (%) 49 (96) 24 (92.4) Staging system Stage 1 n (%) 11 (21.6) 0 0.021cStage 2 n (%) 13 (25.5) 10 (38.5) Stage 3 n (%) 27 (52.9) 16 (61.5) n, number of patients; PICU, pediatric intensive care unit; pRIFLE, pediatric risk, injury, failure, loss, end stage renal disease. a Statistical analysis. o y b Mann---Whitney’s U test. c Fisher’s exact test. Patients’ laboratory data and evolution are shown in Table 2. Hypoalbuminemia was observed in 28.3% and metabolic acidosis in 90.7% (68/75) of patients. The mortality rate was 33.7% (26/77). Eleven patients had disseminated intravascular coagulation, and ten died (one had acute respiratory syndrome and one had multiple organ failure). b m p Table 2 Laboratory features and evolution of patients with sepsi Variable Survived (n = 51 Creatinine (mg/dL, median) 1.39 Urea (mg/dL, median) 111 Albumin (g/dl, mean ± SD) 3.13 ± 0.93 Bicarbonate (mEq/L, mean ± SD) 7.39 ± 5.29 Calcium (mg/dL, median) 8.6 Hypocalcemia (n) 19 Potassium (mEq/L, median) 4 Hyperkalemia (n) 6 Hypokalemia (n) 14 Sodium (mEq/L, median) 138 Hyponatremia (n) 10 Glucose (mg/dL, median) 121 Hypoglycemia (n) 1 Hyperglycemia (n) 11 Hematocrit (%, mean ± SD) 28.7 ± 5.81 Thrombocytopenia (n) 3 Proteinuria (n) 29 n, number of patients. a Statistical analysis. b Mann---Whitney’s U test. c Fisher’s exact test. At the univariate analysis, the factors PICU length of stay, ligo-anuria, invasive mechanical ventilation, need for dial- sis, AKI stage 2 and 3 criteria, hypoalbuminemia, serum icarbonate, and thrombocytopenia were associated with ortality. In the multiple logistic regression analysis, the inde- endent risk factors associated with mortality were PICU s and acute kidney injury. ) Deceased (n = 26) pa 1.69 0.27b 89 0.40b 2.30 ± 0.70 0.006b 11.11 ± 6.58 0.01b 8.45 0.62b 7 0.99c 3.9 0.53b 3 1.00c 9 0.70c 138 0.44b 11 0.065c 110 0.53b 3 0.29c 8 0.98c 29.9 ± 4.9 0.37b 8 0.015c 10 1.00c 32 Riyuzo MC et al. Days of PICU stay 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Kaplan-Meier survival curve estimated by hypoalbuminemia 100 75 50 25 0 Without hypoalbuminemia: With hypoalbuminemia: % s ur vi va l Figure 1 Survival curve in AKI related to hypoalbuminemia. 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 100 75 50 25 0 Without dialysis: With dialysis: Days of PICU stay Kaplan-Meier survival curve estimated by dialysis % s ur vi va l ve in l p S d p 9 ( u p C S s w p 7 p t S m p 9 i S ( ( ( i A ( D A 7 h i c d e m e Figure 2 Survival cur ength of stay (OR = 0.615 SE = 0.1377, 95% CI = 0.469---0.805, = 0.0004), invasive mechanical ventilation (OR = 14.599, E = 1.1178, 95% CI = 1.673---133.7564, p = 0.0155), need for ialysis (OR = 9.714, SE = 0.8088, 95% CI = 1.990---47.410, = 0.0049), hypoalbuminemia (OR = 10.484 SE = 1.1147, 5% CI = 1.179---93.200, p = 0.035), and serum bicarbonate OR = 1.231, SE = 0.0735, 95% CI = 1.066---1.422, p = 0.0046). Other variables were not associated with mortality: olig- ria, anuria (OR = 1.13, SE = 0.1302 95% CI = 0.881---1.467, = 0.32), thrombocytopenia (OR = 1.469, SE = 1.0595, 95% I = 0.184---11.718, p = 0.72), and AKI stage (OR = 0.060, E = 2.2017, 95% CI ≤0.001---4.557, p = 0.20). The estimated probabilities of survival during the PICU tay were 25% in hypoalbuminemic patients, when compared ith 75% in patients with normal albumin (log rank = 5.88, = 0.015) and 24% in patients requiring dialysis compared to 6% of patients who did not need dialysis (log rank = 8.513, = 0.0035; Figs. 1 and 2). In the survival analysis using Cox model, the parameters hat influenced survival were: need for dialysis (HR = 2.952, E = 0.44862, 95% CI = 1.225---7.112, p = 0.016), hypoalbu- inemia (HR = 3.326, SE = 0.59474, 95% CI = 1.037---10.670, = 0.043), and serum bicarbonate (HR = 1.097, SE = 0.04098, 5% CI = 1.042---1.198, p = 0.024). Need for invasive mechan- cal ventilation did not influence survival (HR = 2.424, E = 1.07710, 95% CI = 0.294---20.016, p = 0.411). r a a AKI related to dialysis. The median of days to AKI improvement was five days range 2---21 days) in patients with AKI stage 1; seven days 3---19 days variation) in patients with stage 2; and eight days 3---21 days variation) in patients with stage 3. AKI recovery n the first week occurred in 72.7% (8/11) of patients with KI stage 1, 61.5% (8/13) of patients with stage 2, and 48.1% 13/27) of patients with stage 3. iscussion n association between sepsis and AKI was observed in 1.03% of the patients admitted to this PICU; these patients ad a high mortality rate (33.7%), similar to that described n other studies.4,8,13,28---31 There is a high incidence of sepsis-associated AKI in ritically-ill patients.31 The identification of severe AKI pre- ictive factors has the potential to optimize treatment.31,32 Among the factors associated with mortality, the pres- nce of oliguria or anuria, need for dialysis, need for echanical ventilation, and hypoalbuminemia should be mphasized. Oliguria and anuria increased by 2.24 and 1.9 times the isk of mortality, respectively29; the latter is associated with high mortality rate.10,16 In the present study, oliguria was risk factor for mortality in the univariate analysis, but w h p d c k 4 p w ( t s t c w a s w m a s n t t t e u s i l i o r o t s t c t s p t fi e C T Acute renal injury in children with sepsis did not remain as such in the multivariate analysis. The lower proportion of oligo-anuric patients must have influ- enced the statistical analysis. Most of the present patients were non-oliguric, different from what was observed in the aforementioned studies. The presence of oliguria makes the disease more severe, hindering fluid administration, thus facilitating the development of hypervolemia, which com- plicates the underlying disease.31 The need for dialysis increased by 3.76 times the risk of mortality in children with AKI,29 especially in patients undergoing dialysis for longer periods.9 The present data are consistent with the aforementioned studies.9,29 Need for mechanical ventilation was associated with mor- tality in patients with AKI unrelated to primary urinary tract disorder9,23 and in those with prerenal and non-prerenal AKI11,29; the present findings are consistent with these studies.9,11,23 Patients with sepsis-associated AKI are more likely to require mechanical ventilation and hemodynamic support with vasoactive therapy, and to receive large vol- umes of fluid for resuscitation.31 This fact contributes to longer hospital stay in the PICU and increased mortality.33 In the present study, patients with decreased serum bicarbonate levels had higher survival. In the literature, the presence of acidosis was not an independent factor for the mortality of patients with AKI.24 The present study was con- ducted in a tertiary institution that is a reference center for medical or surgical critically-ill patients, who had probably been treated for acidosis with bicarbonate solutions before arrival at this service. Hypoalbuminemia was associated with higher mortality in pediatric patients.12 In 228 pediatric patients with AKI, serum albumin was higher among survivors (3.3 ± 0.9 g/dL) than in non-survivors (2.6 ± 0.7 g/dL).12 Hypoalbumine- mia may result from accelerated protein catabolism of metabolic alterations in AKI.30 Moreover, albumin synthe- sis is suppressed in response to inflammatory conditions,34 and inflammatory mediators are involved in children with sepsis.21,31 In children with severe disease, hypoalbumine- mia was associated with high mortality and longer time of mechanical ventilation.35 The classification of renal injury severity has been asso- ciated with increased hospital length of stay and increased in-hospital relative mortality risk.31 According to the pRI- FLE criteria, the patients in the present study had severe AKI (most were classified as pRIFLE F). In contrast, the stag- ing criterion showed an even distribution between stages 1, 2, and 3. This fact must be associated with differences in the use of parameters to define AKI. The pRIFLE crite- ria used CrCl and the staging criteria used the increase in serum creatinine levels. Evidence suggests that small changes in serum creatinine are associated with increased patient mortality.18 Other authors have found significant dif- ferences in AKI severity distribution when serum creatinine increase was used instead of CrCl to define AKI; the latter showed greater sensitivity.14,16,18 Patients with pRIFLE I or F at admission showed a two-fold higher risk of mortality, when compared to patients with pRI- FLE R.13,17 No association was observed between the strata of pRIFLE criteria and mortality, similar to the data reported by Plötz et al.15 When the AKI staging criterion was applied to the present patients, results similar to those reported by Ozçakar et al.19 R 33 ere observed. The mortality rate was 33%, and it was igher in patients with AKI stage 2 and 3, similar to the resent results. In sepsis-associated AKI, the probability of eath was higher in patients classified as stage 3 AKI, when ompared with those classified as stage 1.31 Studies have shown an association between the degree of idney disease severity and improvement in renal function: 6% of patients showed renal function recovery within 48 h, redominating in 62.5% patients with pRIFLE R at admission, hen compared to those with pRIFLE I (38.1%) or pRIFLE F 26.7%).13 The recovery from AKI in the first week, according o the staging criterion, occurred in all patients with AKI tage 1, in half of the patients with stage 2, and in one- hird of patients with stage 3.19 The present results were onsistent with the aforementioned studies. The assessed predictive factors of mortality in children ith sepsis-associated AKI comprised clinical, laboratory, nd AKI classification parameters. There is no single consen- us on which parameter is ideal for early diagnosis of AKI, hich would imply in early-onset therapy aimed at reducing ortality. The constant monitoring of critically-ill patients, ssessing the presence of oliguria, hypertension or hypoten- ion, and hypoalbuminemia, as well as the evolution to the eed for mechanical ventilation and/or dialysis, should raise he early suspicion of AKI development. At the same time, he AKI classification should be routinely carried out since he first day of hospitalization, and on the third day for the arly detection of AKI, according to parameter evolution.31 Authors have validated the Renal Angina Index (RAI) sing the product of the risk factors (admission to PICU --- core 1, stem cell transplantation --- score 3, ventilation and notropics --- score 5) and the injury factors (death rate evo- ution associated with fluid overload percentage, decrease n the estimated creatinine clearance, percentage of fluid verload---score ranging from 1, 2, 4, and 8), whose RAI value anges from 1 to 40.32 The RAI cutoff value ≥8 is indicative f high risk for AKI. The present study has limitations, such as the observa- ional retrospective design with a small number of patients tudied in a single center; however, this cohort included he evaluation of AKI in pediatric patients with a specific ondition, i.e., sepsis. The small number of patients with he pRIFLE I classification may have influenced the power of tatistics. It can be concluded that the mortality rate is high in atients with sepsis and AKI; the predictive factors related o mortality were easy to apply, as well as the AKI classi- cation by the staging system or pRIFLE and reflected the volution of patients with sepsis and AKI. onflicts of interest he authors declare no conflicts of interest. eferences 1. Andreoli SP. Acute kidney injury in children. Pediatr Nephrol. 2009;24:253---63. http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0180 3 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 4 2. Gokcay G, Emre S, Tanman F, Sirin A, Elcioglu N, Dolunay G. An epidemiological approach to acute renal failure in children. J Trop Pediatr. 1991;37:191---3. 3. Moghal NE, Brocklebank JT, Meadow SR. A review of acute renal failure in children: incidence, etiology and outcome. Clin Nephrol. 1998;49:91---5. 4. Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemi- ology at a tertiary care center from 1999 to 2001. Am J Kidney Dis. 2005;45:96---101. 5. Bailey D, Phan V, Litalien C, Ducruet T, Mérouani A, Lacroix J, et al. Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study. Pediatr Crit Care Med. 2007;8:29---35. 6. Anochie IC, Eke FU. Acute renal failure in Nigerian children: Port Harcourt experience. Pediatr Nephrol. 2005;20:1610---4. 7. Duzova A, Bakkaloglu A, Kalyoncu M, Poyrazoglu H, Delibas A, Ozkaya O, et al. Etiology and outcome of acute kidney injury in children. Pediatr Nephrol. 2010;25:1453---61. 8. Vachvanichsanong P, Dissaneewate P, Lim A, McNeil E. Childhood acute renal failure: 22-year experience in a university hospital in southern Thailand. Pediatrics. 2006;118:e786---91. 9. Otukesh H, Hoseini R, Hooman N, Chalian M, Chalian H, Tabar- roki A. Prognosis of acute renal failure in children. Pediatr Nephrol. 2006;21:1873---8. 0. Loza R, Estremadoyro L, Loza C, Cieza J. Factors associated with mortality in acute renal failure (ARF) in children. Pediatr Nephrol. 2006;21:106---9. 1. Gallego N, Gallego A, Pascual J, Liaño F, Estepa R, Ortuño J. Prognosis of children with acute renal failure: a study of 138 cases. Nephron. 1993;64:399---404. 2. Williams DM, Sreedhar SS, Mickell JJ, Chan JC. Acute kidney fail- ure: a pediatric experience over 20 years. Arch Pediatr Adolesc Med. 2002;156:893---900. 3. Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int. 2007;71:1028---35. 4. Zappitelli M, Parikh CR, Akcan-Arikan A, Washburn KK, Moffett BS, Goldstein SL. Ascertainment and epidemiology of acute kid- ney injury varies with definition interpretation. Clin J Am Soc Nephrol. 2008;3:948---54. 5. Plötz FB, Bouma AB, van Wijk JA, Kneyber MC, Bökenkamp A. Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria. Intensive Care Med. 2008;34: 1713---7. 6. Kavaz A, Ozçakar ZB, Kendirli T, Oztürk BB, Ekim M, Yalçinkaya F. Acute kidney injury in a paediatric intensive care unit: comparison of the pRIFLE and AKIN criteria. Acta Paediatr. 2012;101:e126---9. 7. Soler YA, Nieves-Plaza M, Prieto M, García-De Jesús R, Suárez- Rivera M. Pediatric risk, injury, failure, loss, end-stage renal disease score identifies acute kidney injury and predicts mor- tality in critically ill children: a prospective study. Pediatr Crit Care Med. 2013;14:e189---95. 8. Bagga A, Bakkaloglu A, Devarajan P, Mehta RL, Kellum JA, Shah SV, et al. Improving outcomes from acute kidney injury: report of an initiative. Pediatr Nephrol. 2007;22:1655---8. 9. Ozçakar ZB, Yalçinkaya F, Altas B, Ergün H, Kendirli T, Ateş C, et al. Application of the new classification criteria of the Acute 3 Riyuzo MC et al. Kidney Injury Network: a pilot study in a pediatric population. Pediatr Nephrol. 2009;24:1379---84. 0. Guignard JP, Santos F. Laboratory investigations. In: Avner ED, Harmon WE, Niaudet P, editors. Pediatric nephrology. 5th ed. Baltimore: Lippincott, Williams and Wilkins; 2004. p. 399---424. 1. Fioretto JR, Borin FC, Bonatto RC, Ricchetti SM, Kurokawa CS, de Moraes M, et al. Procalcitonin in children with sepsis and septic shock. J Pediatr (Rio J). 2007;83:323---8. 2. Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunc- tion in pediatrics. Pediatr Crit Care Med. 2005;6:2---8. 3. Gallego N, Pérez-Caballero C, Gallego A, Estepa R, Liaño F, Ortuño J. Prognosis of patients with acute renal failure without cardiopathy. Arch Dis Child. 2001;84:258---60. 4. Arora P, Kher V, Rai PK, Singhal MK, Gulati S, Gupta A. Prog- nosis of acute renal failure in children: a multivariate analysis. Pediatr Nephrol. 1997;11:153---5. 5. ECC Committee, Subcommittees and Task Forces of the Amer- ican Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005;112. IV1-203. 6. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555---76. 7. Schwartz GJ, Brion LP, Spitzer A. The use of plasma creat- inine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987;34:571---90. 8. Medina Villanueva A, López-Herce Cid J, López Fernández Y, Antón Gamero M, Concha Torre A, Rey Galán C, et al. Acute renal failure in critically-ill children. A preliminary study. An Pediatr (Barc). 2004;61:509---14. 9. Bresolin N, Silva C, Halllal A, Toporovski J, Fernandes V, Góes J, et al. Prognosis for children with acute kidney injury in the intensive care unit. Pediatr Nephrol. 2009;24:537---44. 0. Druml W. Protein metabolism in acute renal failure. Miner Elec- trolyte Metab. 1998;24:47---54. 1. Alobaidi R, Basu RK, Goldstein SL, Bagshaw SM. Sepsis- associated acute kidney injury. Semin Nephrol. 2015;35:2---11. 2. Basu RK, Zappitelli M, Brunner L, Wang Y, Wong HR, Chawla LS, et al. Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children. Kidney Int. 2014;85:659---67. 3. Alkandari O, Eddington KA, Hyder A, Gauvin F, Ducruet T, Gottes- man R, et al. Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study. Crit Care. 2011;15:R146. 4. Moshage HJ, Janssen JA, Franssen JH, Hafkenscheid JC, Yap SH. Study of the molecular mechanism of decreased liver synthesis of albumin in inflammation. J Clin Invest. 1987;79:1635---41. 5. Leite HP, Rodrigues da Silva AV, de Oliveira Iglesias SB, Koch Nogueira PC. Serum albumin is an independent predictor of clin- ical outcomes in critically ill children. Pediatr Crit Care Med. 2016;17:e50---7. http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0185 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0190 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0195 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0200 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0205 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0210 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0215 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0220 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0225 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0230 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0235 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0240 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0245 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0250 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0255 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0260 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0265 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0270 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0275 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0280 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0285 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0290 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0295 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0300 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0305 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0310 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0315 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0320 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http://refhub.elsevier.com/S0021-7557(16)30075-4/sbref0325 http