血液透析之慢性并发症（）课件.ppt

1、血液透析之慢性併發症台北慈濟醫院腎臟內科 洪思群醫師2009-05-10腎性貧血q 腎性貧血的成因及後果q 紅血球生成素q 腎性貧血的治療目標q 紅血球生成素反應不良的因素q 鐵缺乏的診斷與治療q 營養不良、發炎與腎性貧血q 腎性貧血的輔助療法 ImbalanceReduces O2 levels in bloodEPONormal blood oxygen levelsStimulus:HypoxiaImbalanceIncreases O2-carrying ability of blood紅血球生成的調控腎性貧血-紅血球生成素不足慢性腎病各期的貧血盛行率Kausz AT,et al.Di

2、s Manage Health Outcomes 10:505-513,2002 Obrador GT,et al.J Am Soc Nephrol 10:1793-1800,1999腎性貧血的後果貧血之末期腎臟病患有較高之死亡率1.331.121.000.961.251.111.000.9700.20.40.60.811.21.4 27%27%to 30%30%to 33%33%to 500N=333Number of PatientsDose of EPOGEN(U/kg TIW)病患對紅血球生成素的反應Phase 3,multicenter,clinical trial of HD pa

3、tients(N=333).This study was designed to evaluate the safety and efficacy of EPOGEN in patients with uncomplicated anemia.Doses were initiated at 300 or 150 U/kg TIW.When the patients Hct reached 35%,they were placed on the maintenance phase of the protocol and reduced to 75 U/kg TIW.The Hb target r

4、ange for this study was Hct 32%38%(Hb 10.712.8 g/dL).The EPOGEN package insert recommends the Hb not exceed 12 g/dL.Eschbach JW,et al.Ann Intern Med.1989;111:992-1000.EPO反應不良的原因1.Major Iron deficiency Inflammation/Infection Malnutrition Underdialysis 2.Minor HyperparathyroidismAluminum toxicityBlood

5、 loss(often occult)Hemolysis B12/Folate deficiency Marrow disorders Hemoglobinopathy PRCA associated with anti-EPO Ab ACEI 血管形成不良 angiodysplasia 腎性貧血q 腎性貧血的成因及後果q 紅血球生成素q 腎性貧血的治療目標q 紅血球生成素反應不良的因素q 鐵缺乏的診斷與治療q 營養不良、發炎與腎性貧血 q 腎性貧血的輔助療法 造血需要紅血球生成素和鐵Hematopoietic Stem CellBFU-ECFU-EErythroblastsReticuloc

6、ytesErythrocytes(RBCs)(Time to maturity=12 days)Bone MarrowCirculationIron DependentEPO DependentFerritin Iron Transferrin Iron 鐵在人體的吸收與分布細胞之運鐵蛋白循環NKF-K/DOQI 2006 Anemia of Chronic Kidney Disease鐵劑的治療目標q Ferritin(儲鐵蛋白儲鐵蛋白)200 ng/ml q TSAT(運鐵蛋白飽合度運鐵蛋白飽合度)20%診斷鐵缺乏的準則q 絕對絕對鐵缺乏鐵缺乏 TSAT 20%&serum ferriti

7、n 200 ng/ml Increased blood loss;decreased iron absorptionq 功能性鐵缺乏功能性鐵缺乏 TSAT 200 ng/ml RBC production by EPO outstrips iron supplyq 網狀內皮系統阻斷網狀內皮系統阻斷(RE blockade)TSAT 500 ng/ml Acute or chronic inflammation鐵劑給予之劑量絕對絕對鐵缺乏鐵缺乏 Parenteral Iron Therapy 1000 mg given over 8-10 HD treatments to achieve and

8、 maintain K/DOQI targets If No Response A second course of IV iron should be tried(guideline 8 opinion)NKF-K/DOQI Clinical Practice Guidelines for the treatment of CRF AJKD 2001;37(suppl 1)診斷鐵缺乏的準則q 絕對絕對鐵缺乏鐵缺乏 TSAT 20%&serum ferritin 200 ng/ml Increased blood loss;decreased iron absorptionq 功能性鐵缺乏功能

9、性鐵缺乏 TSAT 200 ng/ml RBC production by EPO outstrips iron supplyq 網狀內皮系統阻斷網狀內皮系統阻斷(RE blockade)TSAT 500 ng/ml Acute or chronic inflammation鐵劑給予之劑量功能性鐵缺乏功能性鐵缺乏 Parenteral Iron Therapy 25 to 125 mg once per week in order to provide 250 to 1000 mg within 12 weeks (guideline 8 opinion)NKF-K/DOQI Clinical

10、 Practice Guidelines for the treatment of CRF AJKD 2001;37(suppl 1)681012140481216Hemoglobin(g/dl)All 37 patients entered study iron replete with Hb 8.5 g/dl *P0.05 vs.EPO+IV iron*P0.005 vs.EPO+IV ironEPO onlyEPO+Oral IronEPO+IV Iron*WeeksMacdougall et al.Kidney Int 1996鐵劑給予之途徑EPO doseU/kg/wk6 month

11、sSunder-Plassmann et al.J Am Soc Nephrol 1994 靜脈鐵劑降低EPO使用量IV Fe TherapyYear of National Dialysis Surveillance19951996199719981999Epo Use(%patients)020406080100Mean Hematocrit(%)26272829303132Epo UseHematocrit26.827.227.528.028.982.778.076.577.574.0Taiwan Soc Nephrol Annual Report 2003 台灣慢性血液透析病患EPO用

12、量和Hct之趨勢變化SerumSerumSerumTSATTSATPercent of Patients0204060801001995199619971998199951413229273236404546172327262727232119187377798182ferritin 800 g/l 20%台灣慢性血液透析病患Ferritin和TSAT之趨勢變化Taiwan Soc Nephrol Annual Report 2003 Cost effective Free radical Infection 使用鐵劑的正反兩面效應IronDrueke,T.et al.Circulation

13、106:2212-17,2002接受鐵劑劑量與頸動脈厚度之相關性Kalantar-Zadeh K,J Am Soc Nephrol 16:3070-3080,2005接受鐵劑劑量與死亡率之相關性NKF-K/DOQI 2006 Anemia of Chronic Kidney Disease鐵劑的治療目標上限q Ferritin(儲鐵蛋白儲鐵蛋白)500 ng/ml q TSAT(運鐵蛋白飽合度運鐵蛋白飽合度)50%J Am Soc Nephrol 18:975-984,2007Ferritin:500-1200TSAT 25%高Ferritin之血液透析病患對鐵劑補充仍有反應診斷鐵缺乏的準則q

14、 絕對絕對鐵缺乏鐵缺乏 TSAT 20%&serum ferritin 200 ng/ml Increased blood loss;decreased iron absorptionq 功能性鐵缺乏功能性鐵缺乏 TSAT 200 ng/ml RBC production by EPO outstrips iron supplyq 網狀內皮系統阻斷網狀內皮系統阻斷(RE blockade)TSAT 500 ng/ml Acute or chronic inflammationHepcidin(肝泌抑菌素)J Am Soc Nephrol 18:394-400,2007 腎性貧血q 腎性貧血的成

15、因及後果q 紅血球生成素q 腎性貧血的治療目標q 紅血球生成素反應不良的因素q 鐵缺乏的診斷與治療q 營養不良、發炎與腎性貧血 q 腎性貧血的輔助療法 MIA 症候群Cytokines(IL-6 and TNF-a)MalnutritionInflammationAtherosclerosisAnaemiaStenvinkel P et al.Nephrol Dial Transplant 15:95360,2000Factors affecting erythropoiesisFactors Affecting ErythropoiesisEffect of Pentoxifylline T

16、reatment on Ex Vivo TNF Production by CD3+T Cells J Am Soc Nephrol 2004Effect of Pentoxifylline Treatment on Hb Levels Cooper et al.J Am Soc Nephrol 2004腎性貧血q 腎性貧血的成因及後果q 紅血球生成素q 腎性貧血的治療目標q 紅血球生成素反應不良的因素q 鐵缺乏的診斷與治療q 營養不良、發炎與腎性貧血 q 腎性貧血的輔助療法 Tarng et al.Nephrol Dial Transplant 2001維他命C可增加鐵的可利用率 腎性貧血的

17、輔佐療法 維他命Cq Hemoglobin 5.5 g/dlq Creatinine 12 mg/dlq Ferritin 75 ng/mlq TSAT 12%應該如何治療?55 y/o female,general malaise,poor appetite,shortness of breath k+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pt8XCh(Lq5Uze%In2RwaZEj-Ns7WBgk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pt8XCh(Lq5Uze%In2RwaZEj-Ns7WBg*Kp

18、4Tyd!Gl0Pu9YDi)Mr6VAf%In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pt8XCh(Lq5Uze%In2RwaZEj-Ns7WBgKp4Tyd!Gl0Pu9YDi)Mr6VAf%In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pt8XCh(Lq5Uze%In2RwaZEj-Ns7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf%In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pt8XCh(Lq5Uze%In

19、2RwaZEj-Ns7WBgKp4Tyd!Gl0Pu9YDi)Mr6VAf%In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pt8XCh(Lq5Uze%In2RwaZEj-Ns7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh

20、(Lq5Uze%In2RwaZEj-Ns7WBgNs7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBgKp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-

21、Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBgKp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBgKp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(K

22、p4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBgNs7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&I

23、n2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBgKp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Kp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwaZEj-Ns7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwbZEj-Ns7WBgKp4Tyd!Gl

24、0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwbZEj-Ns7WBg*Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwbZEj-Kp4Tyd!Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Nr6VAf&Jo3Sxc!Gl0Pu8XCh(Lq5Uze%In2RwbZEj-Ns7WB

25、gNs7WBg*Ks7WBgKs7WBg*Kp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XBgKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XBg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In1QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In1QvaZEj-Ns7WBg*Kp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XBgKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rw

26、b#Fk+Ot8XBg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCgKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Kp4Tyd$Hm1QvaZEi)Mr6

27、VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgNs7WBg*Kp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCgKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XC

28、gKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCgKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%

29、In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCgKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgNs7WBg*Kp4Sxc!Gl

30、0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCgKp4Sxc!Gl0Pu9YDi)Mr6Vze%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEi)Mr6VAf&Jo3Sxc!Gl+Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Txc!Gl0Pu9YDi)Mr6VDi)Mq5Uze%In2Rwb#Fk+Ot7WBgKp4Txc!Gl0Pu9YDi)Mr6VDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4T

31、yd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgKp4Tyd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBg*Jo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBgJo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Kp4Tyd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot

32、8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgNs7WBg*Jo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBgJo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgKp4Tyd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBg*Jo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBgJo3Sxc!Gl0Pu9YD

33、i)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgKp4Tyd$Hm1Qv9YDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBg*Ko3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBgKo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Kp4Tyd

34、$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgNs7WBg*Ko3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBgKo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgKp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBg*Ko3Sxc!Gl0Pu9YDi)Mq5Uze%I

35、n2Rwb#Fk+Ot7WBgKo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgKp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBg*Ko3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBgKo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+

36、Ot8XCh(Lq5Uze%Hm1QvaZEj-Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgNs7WBg*Ko3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBgKo3Sxc!Gl0Pu9YDi)Mq5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBgKp4Tyd$Hm1Qv

37、aYDi)Mr6VAf&Jo3Sxc#Fk+Ot8XCh(Lq8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBg*Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBgKp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rw

38、b#Fk-Ns7WBg*Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBgNs7WBg*Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu

39、9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBgKp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBg*Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBgKp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Rwb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7

40、WBf&Jo3Sxc!Gl0Pu9YDh(Lq5Uze%In2Rwb#Fk-Ns7WBg*Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Swb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDi(Lq5Uze%In2Rwb#Fk-Ns7WBgKp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Swb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDi(Lq5Uze%In2Rwb#Fk-Ns7WBg*Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Swb#Fk+Ot8XCh(Lq5

41、Uyd$Hm1QvaZEj-Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Swb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDi(Lq5Uze%In2Rwb#Fk-Ns7WBgNs7WBf&Jo3Sxc!Gl0Pu9YDi(Lq5Uze%In2Rwb#Fk-Ns7WBg*Kp4Tyd$Hm1Pu9YDi)Mr6VAf&Jo3Swb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDi(Lq5Uze%In2Rwb#Fk-Ns7ZEj-Ns7WBgKp4Tyd$Hm1Pu9YDi)Mr6V

42、Af&Jo3Swb#Fk+Ot8XCh(Lq5Uyd$Hm1QvaZEj-Ns7WBf&Jo3Sxc!Gl0Pu9YDi(Lq5Uze%In2Rwb#Fk-Ns7ZEj-Ns7WBg*Kp4Tyd$Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Gl0Pu9XCh(Lq5Uze%In2RwbZEj-Ns7WBgKp4Tyd$Gl0Pu9YDi)Mr6VAf&In2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Gl0Pu9XCh(Lq5Uze%In2RwbZEj-Ns7W

43、Bg*Kp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Gl0Pu9XCh(Lq5Uze%In2RwbZEj-Kp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Gl0Pu9XCh(Lq5Uze%In2RwbZEj-Ns7WBgNs7WBg*Kp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Gl0Pu9XCh(Lq5U

44、ze%In2RwbZEj-Ns7WBgKp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Gl0Pu9XCh(Lq5Uze%In2RwbZEj-Ns7WBg*Kp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Gl0Pu9XCh(Lq5Uze%In2RwbZEj-Ns7WBgKp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sx

45、c!Gl0Pu9XCh(Lq5Uze%In2RwbZEj-Ns7WBg*Kp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Go3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Kp4Tyd$Gl0Pu9YDi)Mr6VAf&Jn2Rwb#Fk+Ot8XCh(Lp4Tyd$Hm1QvaZEj-Ns6VAf&Jo3Sxc!Go3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgNs7WBg*Kp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XC

46、gKp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCgKp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%

47、In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCgKp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Txc!Gl

48、0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCgKp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Kp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgNs7WBg*Kp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCgKp4Txc!Gl0Pu9YDi)Mr6VAe%In2Rwb#Fk+Ot8XCg*Kp4Tyd$Hm1QvaZEj)M

49、r6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBgKp4Tyd$Hm1QvaZEj)Mr6VAf&Jo3Sxc!Gl0Ot8XCh(Lq5Uze%In2QvaZEj-Ns7WBg*Kp4Txc!Gl0Pu9YDi)Mr9YDi)Mr5Uze%In2Rwb#Fk+Ot7WBgKp4Txc!Gl0Pu9YDi)Mr9YDi)Mr5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc!Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBgKp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc!Fk+Ot8XCh(Lq5Uze%Hm1QvaZEj-Ns7WBg*Ko3Sxc!Gl0Pu9YDi)Mr5Uze%In2Rwb#Fk+Ot7WBgKo3Sxc!Gl0Pu9YDi)Mr5Uze%In2Rwb#Fk+Ot7WBg*Kp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc!FKp4Tyd$Hm1QvaYDi)Mr6VAf&Jo3Sxc!F