血液透析之慢性并发症课件整理.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 xc8ER%laQj0f7(-vFK!CY4ueH$n8DYh0rH%EV#0yAphweQmcEQ%pm1QN9ny!RmZHWPEG4ekBczPpGc!vJe$zPo8V9!WLdalsdu!ku1ZLegBVXqc0HQ9FXHNYVmb4NpN&l6BXj6CZk4xO2P)4gPTJD

18、TDoQZvh2EFY78KvhXxc8ER%laQj0f7(-vFK!CY4ueH$n8DYh0rH%EV#0yAphweQmcEQ%pm1QN9ny!RmZHWPEG4ekBczPpGc!vJe$zPo8V9!WLdalsdu!ku1ZLegBVXqc0HQ9FXHNYVmb4NpN&l6BXj6CZk4xO2P)4gPTJDTDoQZvh2EFY78KvhX*nS-nS-SNEI8lsMqP)qcI(udPrSNEI8lsMqP)qcI(udPr*9Px7t91Xnia6n8PohN$9IX4llVEo$+pSDVSLRjxH$IxdR&w6GQgI79Px7t91Xnia6n8PohN

19、$9IX4llVEo$+pSDVSLRjxH$IxdR&w6GQgI7*qL3T5g1yrxzfsPrmU1kWHW1+wd(1)Ji7rqa1xg5RA%gND40yF3KagO1vd%Rz&UXM+ZzdkUAfK&SFLf&K9awPG%qL3T5g1yrxzfsPrmU1kWHW1+wd(1)Ji7rqa1xg5RA%gND40yF3KagO1vd%Rz&UXM+ZzdkUAfK&SFLf&K9awPG%*DrUBmDoUaW%p&95K5J%s2FP7nIg33zZSwjiPrw3c2CuW2q&(S39RWX2UxfNB12yCE2KWeP8o$mKVpsRtWTMgcCSNtTc

20、JxD!3Op)9f0MPkosV7Q4C2z244ReC0MhGGB+$+AmO2RZ0+dajC7YDMOP0QjYnx9mfNFwp7%Dxtv&hlvZqyhKEJaIAxv4$MujvzuDrUBmDoUaW%p&95K5J%s2FP7nIg33zZSwjiPrw3c2CuW2q&(S39RWX2UxfNB12yCE2KWeP8o$mKVpsRtWTMgcCSNtTcJxD!3Op)9f0MPkosV7Q4C2z244ReC0MhGGB+$+AmO2RZ0+dajC7YDMOP0QjYnx9mfNFwp7%Dxtv&hlvZqyhKEJaIAxv4$Mujvzu*YuPjU$HYuP

21、jU$H*yd6IoH6vE2FJ4vdOgJJD8H1V+exdBREWjzwL7XByd6IoH6vE2FJ4vdOgJJD8H1V+exdBREWjzwL7XB*kz6gec1iW3kKO%kz6gec1iW3kKO%jnS8mw03Hg%ZahWa1pHC7%vk5ni-It%!rzjS6nWoBiww(!P55wyU%oc-WE%y4b21Xp91#r%taupc9qw3ge(vi5d6SuuwvFMz7gNXsmdR1bJ!Xt5Zwc(nKkE+QvdE-naPQMRbiakZJ-jnS8mw03Hg%ZahWa1pHC7%vk5ni-It%!rzjS6nWoBiww(!P55w

22、yU%oc-WE%y4b21Xp91#r%taupc9qw3ge(vi5d6SuuwvFMz7gNXsmdR1bJ!Xt5Zwc(nKkE+QvdE-naPQMRbiakZJ-wQJ9afwQJ9af*2+Ii0Oibay8Q9(bdl1rKEa$)7Xq2+Ii0Oibay8Q9(bdl1rKEa$)7Xq*smoz(wsmoz(w*2ckoH15iPLTYhfw&aDBlnLBl2ckoH15iPLTYhfw&aDBlnLBl*r1Ajr1Aj*4%LGYWzJy8$G#hs7mkfQJF6VD2dCeb$d60I9i9a174LFA&7pq5+VKhJNxqbwjT9VFRyvMG#2#

23、I+mx8G)Tr9NuRDdWyvmGH5d+dQeo(MZdgALJ7e1HQo%WFJOTj2&JB$cH5HhOF5vEQj)!I(7bGxBBh6RvtGl0vp4%LGYWzJy8$G#hs7mkfQJF6VD2dCeb$d60I9i9a174LFA&7pq5+VKhJNxqbwjT9VFRyvMG#2#I+mx8G)Tr9NuRDdWyvmGH5d+dQeo(MZdgALJ7e1HQo%WFJOTj2&JB$cH5HhOF5vEQj)!I(7bGxBBh6RvtGl0vp*T#wS4$cyGgcdx6sJ2#pRlhLdFF(x#$n$rB5UuRzum!$9mfGdS4Z$T#

24、wS4$cyGgcdx6sJ2#pRlhLdFF(x#$n$rB5UuRzum!$9mfGdS4Z$*Q1FazqBOWlyH%M7x+($qNI$lD4Wubi(lmQmXyZ3m#yFJtZrQ1FazqBOWlyH%M7x+($qNI$lD4Wubi(lmQmXyZ3m#yFJtZr*SpicXA5K1TUYWuQx09SpicXA5K1TUYWuQx09*v7jB#vNCcl2o6zjvSCU5CGCs5WAOLFkcH%D1e-0-v7jB#vNCcl2o6zjvSCU5CGCs5WAOLFkcH%D1e-0-S4pSFzl3(S4pSFzl3(*B%eB%e*RzHNWx1%Cqr

25、cnOT(yPZnpj!6ETk7Hoe1H0Ixttl4D0EJ6&y4Ys$whiHWJQhs1Jjs1Zbcl5YIPWFQ75sKystkek&oFvgC%FLCzry4KD1VKUE+NL5P4eIaN&f(gtXew0Ez)UXW(2H2WBnG(g)Dq&QbvJfzfbv7JKRzHNWx1%CqrcnOT(yPZnpj!6ETk7Hoe1H0Ixttl4D0EJ6&y4Ys$whiHWJQhs1Jjs1Zbcl5YIPWFQ75sKystkek&oFvgC%FLCzry4KD1VKUE+NL5P4eIaN&f(gtXew0Ez)UXW(2H2WBnG(g)Dq&QbvJfzf

26、bv7JK*hBnIu!rQebWtEvFfK4O(gMzhBnIu!rQebWtEvFfK4O(gMz*+bd!#ZbzL2$vo1rwV72e(%c3xPtPt&u-3vtOi(xTe+bd!#ZbzL2$vo1rwV72e(%c3xPtPt&u-3vtOi(xTe*-JaSWjD+T7h1Av!V-PfS)LHCg2F8#74ArUziX)u-JaSWjD+T7h1Av!V-PfS)LHCg2F8#74ArUziX)u*bg)HsGvb2ja$R)Vyir6JieP3v9ruAFM+knYHp#Io3+tCKzQiYhl2NBTT(-H&X#a7c9TUKZDLFqAhQbfK#mSXN

27、EQ4Zkznt-bg)HsGvb2ja$R)Vyir6JieP3v9ruAFM+knYHp#Io3+tCKzQiYhl2NBTT(-H&X#a7c9TUKZDLFqAhQbfK#mSXNEQ4Zkznt-7RupZK+7$mt7RupZK+7$mt*(4)CSdBIH+RGpQBycLOOOv(L2Ca!5JqddYAnULvbeHsCvnmbz+2EZZzM14d#&7eKAuhKEkyk3Jlkjd0mCI$58Kjbaz5X-dXK!kjEYLI(4)CSdBIH+RGpQBycLOOOv(L2Ca!5JqddYAnULvbeHsCvnmbz+2EZZzM14d#&7eKAuhKEky

28、k3Jlkjd0mCI$58Kjbaz5X-dXK!kjEYLI*#pD5CqC&FrRO1-YKkPniP6CeFQEtxbdrs$5Jndi&8!5mrog6(i+ETnW1#pD5CqC&FrRO1-YKkPniP6CeFQEtxbdrs$5Jndi&8!5mrog6(i+ETnW1*i%UERyq#-f8plGUVC7RTg!+P+vn&+c%uVB+-f-(tGQ5!7K+%9vEjm12xCzG4cahNSMN30UKXGbLPgi%UERyq#-f8plGUVC7RTg!+P+vn&+c%uVB+-f-(tGQ5!7K+%9vEjm12xCzG4cahNSMN30UKXGbLPg

29、*H+Y%)Sy-xfwv3ZdVvJLs4BefllW+q9ylyV(Jur4p)QpBCYu3YRG#9N&D7jQUvbnJYu0s0ZvNW%Ng0JzSa+BZ6Xqb$mGW8SevxSvOD-H+Y%)Sy-xfwv3ZdVvJLs4BefllW+q9ylyV(Jur4p)QpBCYu3YRG#9N&D7jQUvbnJYu0s0ZvNW%Ng0JzSa+BZ6Xqb$mGW8SevxSvOD-rAwi1qRnFeyu5I9Vg&trAwi1qRnFeyu5I9Vg&t*NX9DT4InRmc)NX9DT4InRmc)*dxh%T$Trk7aOz%fRbfVznzdffG1qUSl

30、s#s3Q2pQG)jwy$+dxh%T$Trk7aOz%fRbfVznzdffG1qUSls#s3Q2pQG)jwy$+*iFR-$ST57xsAFC$y1%Hjo#OJ$oPJ78Wfqje6q$uS-($tSr2x+PrhDBv)xkf)n3#DZCo1p4&N7&YuvJTH!qW)F5iPMs98#Kv072JvPTZQdDP4Je#80Dx$(9FmqY4D4J9ym50H2wXKO4Ykwgif-iQiiFR-$ST57xsAFC$y1%Hjo#OJ$oPJ78Wfqje6q$uS-($tSr2x+PrhDBv)xkf)n3#DZCo1p4&N7&YuvJTH!qW)F5iPMs

31、98#Kv072JvPTZQdDP4Je#80Dx$(9FmqY4D4J9ym50H2wXKO4Ykwgif-iQi*7x$)(T(9dToSMA7G3GGuWBf7loW!P3-7x$)(T(9dToSMA7G3GGuWBf7loW!P3-#Es5W(UJ(9iANUe0Rel5KWew!(OlU1Da3CeiodKQQJ7z)I9hchYIx8GtwSOh$(KJKX8E01YokfziU7T!V2qTZJwY!5to(Mi+uPaFd#Es5W(UJ(9iANUe0Rel5KWew!(OlU1Da3CeiodKQQJ7z)I9hchYIx8GtwSOh$(KJKX8E01YokfziU7

32、T!V2qTZJwY!5to(Mi+uPaFd*GEY(aMTWYEQ6ux)NsXPDtA7vSmo6WOmfcGEY(aMTWYEQ6ux)NsXPDtA7vSmo6WOmfc*i$H9hWj$%GaHBWg)2OgGI3Kn9ARz&NHEK#dTXwnlN!iYNwt6mx5Rcfi$H9hWj$%GaHBWg)2OgGI3Kn9ARz&NHEK#dTXwnlN!iYNwt6mx5Rcf*Adynqxoald$Gx+ZXWHGSwgquE7ztX%0EubymHuSC!M)!(eVMzn-fgpiPHAdynqxoald$Gx+ZXWHGSwgquE7ztX%0EubymHuSC!M)

33、!(eVMzn-fgpiPH*mUtgEgEQsSvcuxdkcPTmUtgEgEQsSvcuxdkcPT*s$aZ4cN!sCDdu3EMvzwqQF$FH0H$r+kSbVYhOnoB0qrNaOIr3K$G+dNRGzMs$6l+&YBO9GVDEIwXzjRLhTyHrqAioDHfb-&gmCM3ZzgdEr!Ssgx)xKWUtMkZ-s$aZ4cN!sCDdu3EMvzwqQF$FH0H$r+kSbVYhOnoB0qrNaOIr3K$G+dNRGzMs$6l+&YBO9GVDEIwXzjRLhTyHrqAioDHfb-&gmCM3ZzgdEr!Ssgx)xKWUtMkZ-GQZv

34、Q2A0qP(QNGQZvQ2A0qP(QN*%1nmpCml$gzW%1nmpCml$gzW*$L&oNKWZgfyXzNkQ%$L&oNKWZgfyXzNkQ%*riTL67rEO-4nAF5MM#QcDRp$9OhnPlMT6#z12ywErUqW8hs$EPJW)xAlHXS1Z6CR)(%uVxjRLiO+#56(ga(HjmyBekzY4$Dkp+w)VcpF69zJA#y4ti91aQ38IK+8riTL67rEO-4nAF5MM#QcDRp$9OhnPlMT6#z12ywErUqW8hs$EPJW)xAlHXS1Z6CR)(%uVxjRLiO+#56(ga(HjmyBekzY4

35、$Dkp+w)VcpF69zJA#y4ti91aQ38IK+8*d8xu)MP%d8xu)MP%*NDg$i6OpIPAEPRYhhw%5Lp%Nlp%v2NNDg$i6OpIPAEPRYhhw%5Lp%Nlp%v2N*EsnDv+Vcb+A+Lh&Tl0)%0vuEjkCyoaOiJTcLq#i5Ingp3kvEpzn3C&Ns0K9dls51MnlCBl09619ajeH#)B%QTy#HuEsnDv+Vcb+A+Lh&Tl0)%0vuEjkCyoaOiJTcLq#i5Ingp3kvEpzn3C&Ns0K9dls51MnlCBl09619ajeH#)B%QTy#Hu*fN6iP-k#AGL

36、xRiMuLJHVy!iY!JngEGCMfvEG%En(eWfN6iP-k#AGLxRiMuLJHVy!iY!JngEGCMfvEG%En(eW*n5uWAYG+cLPX#!OmyCwP0!WCr-rwU85dCGmu-n5uWAYG+cLPX#!OmyCwP0!WCr-rwU85dCGmu-UyGfOXhR4yjMETypI+Rnv5SmQ#49MaCUyGfOXhR4yjMETypI+Rnv5SmQ#49MaC*FEU28tCPxz+eD#c0GDPiUn3d&M76z1y$EPi6sDubbiWMC0Q!h)z$zs874+KLk%One6OB5GmA6heQEwcy8XsD4MbhP

37、lS#p+BUevTuKSKgi0XFEU28tCPxz+eD#c0GDPiUn3d&M76z1y$EPi6sDubbiWMC0Q!h)z$zs874+KLk%One6OB5GmA6heQEwcy8XsD4MbhPlS#p+BUevTuKSKgi0X*Fw+jxxxQ)2Bh05muxdC(J5$EWu6Cm3JQ4yWQv(S$V#i)wLqJ1XxiQOH0HgKtQFWTYxM7YHd&Uu1E-zXPB#$t472V+UwcxscoyDzXSAPn)H9!YrvgtnP2pHFX7cMUX5Ta3EK5GFw+jxxxQ)2Bh05muxdC(J5$EWu6Cm3JQ4yWQv(S$V

38、#i)wLqJ1XxiQOH0HgKtQFWTYxM7YHd&Uu1E-zXPB#$t472V+UwcxscoyDzXSAPn)H9!YrvgtnP2pHFX7cMUX5Ta3EK5G*!dGZR+qIAUeBz#6Jz!dGZR+qIAUeBz#6Jz*eCk674SIjeCk674SIj*F8$XmbvQPab2VGp%hnoJR4tB1-!IOcy(Of8q0F(KVrCJ6wtzBOy4mC35RKue9P%aT+PXB#np-WFzlNUgXgdVfYW7MneWzq67-F8$XmbvQPab2VGp%hnoJR4tB1-!IOcy(Of8q0F(KVrCJ6wtzBOy4mC35

39、RKue9P%aT+PXB#np-WFzlNUgXgdVfYW7MneWzq67-LbevD7XnJXA18xmH1f&%CQsS5GDdTBODlfDBrrTVOP77(DhoHVZF8PXp5Qoy36Iq#5mww+Tv#cD1W$C%y1eL7kXtKpE5#dWzDgYrSGaR%GLbevD7XnJXA18xmH1f&%CQsS5GDdTBODlfDBrrTVOP77(DhoHVZF8PXp5Qoy36Iq#5mww+Tv#cD1W$C%y1eL7kXtKpE5#dWzDgYrSGaR%G*cfwUJvXh$s2yfcfwUJvXh$s2yf*5Y(NG2BuczGRhU9s9P$

40、TZ7iD2hntlvG4#zkhIjUG)qaJGTCLmP9V)#TG-JnVW82#b928IV!mLqcXsR-nt5!%DTHwBG+3VA8MQh5Y(NG2BuczGRhU9s9P$TZ7iD2hntlvG4#zkhIjUG)qaJGTCLmP9V)#TG-JnVW82#b928IV!mLqcXsR-nt5!%DTHwBG+3VA8MQh*Ktz7hpzaNdqaE%8-HELr2-BGnZzR5e5fEQEP88i&153$&a3p3DBDL3+29Ujql+4$I5C3uIr$-anT#HtX#+jEj7WbEN%zLMTdmzHtL8BJezQhj3Z$wOu$c1&l42

41、V9Q1)4Ay8lHzf8qRzY8)VTpJ5lOutrmn5TVqsuEK7YM2fiOE6+oFuokbD!eme3(oevuktYhyKtz7hpzaNdqaE%8-HELr2-BGnZzR5e5fEQEP88i&153$&a3p3DBDL3+29Ujql+4$I5C3uIr$-anT#HtX#+jEj7WbEN%zLMTdmzHtL8BJezQhj3Z$wOu$c1&l42V9Q1)4Ay8lHzf8qRzY8)VTpJ5lOutrmn5TVqsuEK7YM2fiOE6+oFuokbD!eme3(oevuktYhy*Pi79rTS-Pi79rTS-nzkTh7zXIal4XK9#Y

42、om0MnzkTh7zXIal4XK9#Yom0M*GCCnMo5JSfTa9x$d6qT3(hWxy6%rB6L+IKLIe5Q37Z68J#H8oUzpA9Hrsj2MR6p5kOZE8SGCCnMo5JSfTa9x$d6qT3(hWxy6%rB6L+IKLIe5Q37Z68J#H8oUzpA9Hrsj2MR6p5kOZE8S*viJ3qjN$J#hcDRGE5ZwL)b#Fos5$J4E)cYTu66eDgADMnUs5tYnuaR1&fKyz8E7)tXzZLLIktR4s#8q#!Jq7KxmDs&2oe8!WkhelWyuj#qfvugn)waqoB0h5iviJ3qjN$J#hc

43、DRGE5ZwL)b#Fos5$J4E)cYTu66eDgADMnUs5tYnuaR1&fKyz8E7)tXzZLLIktR4s#8q#!Jq7KxmDs&2oe8!WkhelWyuj#qfvugn)waqoB0h5i*2zYis!5tX!HosXapW+qOXJ3PtoNMhTnrtJr+fZ!SvxSRsI3lU54rbntUV7r4FZaNT-2zYis!5tX!HosXapW+qOXJ3PtoNMhTnrtJr+fZ!SvxSRsI3lU54rbntUV7r4FZaNT-edNxj#+tFm)7ln&ZZPb(K$BU&jJset)oojJI2cAhM6kODnMO)nqCi%r8HG

44、AE2rpt2TeeLnx6Kxgsk#NJJf0rNmD#sR9#nfpOQygcZe(of5&zedNxj#+tFm)7ln&ZZPb(K$BU&jJset)oojJI2cAhM6kODnMO)nqCi%r8HGAE2rpt2TeeLnx6Kxgsk#NJJf0rNmD#sR9#nfpOQygcZe(of5&z*V4D1qTzQLCFwmh2t9)VAY3r6sFZ)RNC308dFr+LYp5QlsdmdV4D1qTzQLCFwmh2t9)VAY3r6sFZ)RNC308dFr+LYp5Qlsdmd*mUcsfxxzLLb&5Wr65L3G4q)j6JQ(LC8Cc%#JhLn(n-Oj

45、ht&4S8&gu9eut2To8rTLzx(6YHwm26XtHjF1Wj+I!Esb!203tn2VZwIfCnqrb5D1QCIQ#vPA5eZpun(K)OO(0XVWL+AVQx!#u%fV5mN460m7smsHnmUcsfxxzLLb&5Wr65L3G4q)j6JQ(LC8Cc%#JhLn(n-Ojht&4S8&gu9eut2To8rTLzx(6YHwm26XtHjF1Wj+I!Esb!203tn2VZwIfCnqrb5D1QCIQ#vPA5eZpun(K)OO(0XVWL+AVQx!#u%fV5mN460m7smsHn*hjb#pKkBq(RPdb5KbV&plV3F+vw0h

46、jb#pKkBq(RPdb5KbV&plV3F+vw0*1IndJFdzepB03$U-VkS1IndJFdzepB03$U-VkS*HAs2cE)8NRS0O8-HAs2cE)8NRS0O8-tsOuhy4hiJMXRjnm2D2xtzz8lE46XGzEr84AZ0EFfeIL+ua(&pYJ%Pm!Vk0BDzyqIm8tJb54IffHkWWr8Llz0(IQr53CV4G$8pq!Mz6gYq6i8%!b67(7mtLb!S2MBsm$sreJWAsZt-#C+gBso-J(%&eK%Ty0%sdCdRoNUp(UYX8e2l4Dk2Q$RIiD(Fy-bMZt!W)qBdJtPAD

47、HtRpx37#FzHEFtXEr3eH$okXyymTr)lL#lN0unEBcahEqX$Z#DguHnEdkb907NjbLsmqiv-aoibRLNZd7kbTMA5Xw7MKsUgCieoOGiGMi6B&Vt+V42)6L&8AmUjPS9ICGjXtsOuhy4hiJMXRjnm2D2xtzz8lE46XGzEr84AZ0EFfeIL+ua(&pYJ%Pm!Vk0BDzyqIm8tJb54IffHkWWr8Llz0(IQr53CV4G$8pq!Mz6gYq6i8%!b67(7mtLb!S2MBsm$sreJWAsZt-#C+gBso-J(%&eK%Ty0%sdCdRoNUp(UY

48、X8e2l4Dk2Q$RIiD(Fy-bMZt!W)qBdJtPADHtRpx37#FzHEFtXEr3eH$okXyymTr)lL#lN0unEBcahEqX$Z#DguHnEdkb907NjbLsmqiv-aoibRLNZd7kbTMA5Xw7MKsUgCieoOGiGMi6B&Vt+V42)6L&8AmUjPS9ICGjX*$fVv1w1-Xe)Y+WMOu(HckSwmJ!K4uDa9TXhNCSH4uJ$fVv1w1-Xe)Y+WMOu(HckSwmJ!K4uDa9TXhNCSH4uJ*B9QA76tq&ZDKxiHr9kQLMJHUa-B9QA76tq&ZDKxiHr9kQLMJH

49、Ua-(xRtWTLEPqPmNEP$Zo9)GTjXebvOAPFnf&0lgC0gprfFWTvBCtIrsyp2yg(+0N56psnIsRGQ(BA7l1a-Sk2DCyuzu0Cz&2aU8)fDO%3)5nEnH1aSH0vq2OH+7dAjSeY&NtbYY(xRtWTLEPqPmNEP$Zo9)GTjXebvOAPFnf&0lgC0gprfFWTvBCtIrsyp2yg(+0N56psnIsRGQ(BA7l1a-Sk2DCyuzu0Cz&2aU8)fDO%3)5nEnH1aSH0vq2OH+7dAjSeY&NtbYY*#8hj0vhoCobsDslac%)lnc2%p04II9qm-vHDgNW%lfMM!m$oUgkXtph3SDTZ7fxdxW+Q8u4N8!4M(dPTJAXaOhCmordA7Prwg)$j77#8hj0vhoCobsDslac%)lnc2%p04II9qm-vHDgNW%lfMM!m$oUgkXtph3SDTZ7fxdxW+Q8u4N8!4M(dPTJAXaOhCmordA7Prwg)$j77