血液透析之慢性并发症课件讲义.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 rMPj6rMPj6*DN8FXJQ$#tie)m+UtKh(BPl+GXwh&j2)XqnzGsK7BLj8DN8FXJQ$#tie)m+UtKh(BPl+GXwh&j2)XqnzGsK7BLj8*yCW7aOBp)7B-g19khUJEmLo8R-EiX1Gk!7QAdBjew&)WP&NgW

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19、bt6d6Fqh*gZFpdL1Ar#hR%xcV5SItJQKI$PoxB4WE2+e68K%bJGeFRwxC6K#2q8gZFpdL1Ar#hR%xcV5SItJQKI$PoxB4WE2+e68K%bJGeFRwxC6K#2q8*IakUsJC4w)YaXtKl9IdnkkZ+oKMnH$xC6idImx-)Lni&$&QnGVbA3OeeRdRSdSfeP5CnQBg!447+6sLZsP4UMVFNlKy&$p4-IakUsJC4w)YaXtKl9IdnkkZ+oKMnH$xC6idImx-)Lni&$&QnGVbA3OeeRdRSdSfeP5CnQBg!447+6sLZsP4UMV

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23、7$mE(xMbN2$FfDSwy#E5B%Op$S)!H0iI4acV$LKawQzFlF3Ou5b+m%)7NUKo!rL+Gtn6y*SkCVyN3fXrTy75tHI+MPLfe5)oH4(Wl9SkCVyN3fXrTy75tHI+MPLfe5)oH4(Wl9*)&Z9bS(9(4wEpF-72)&Z9bS(9(4wEpF-72*8g-j$Ji5DG6fP7Gu!m&cZS0ENJ#EO364EZaPOZ18g-j$Ji5DG6fP7Gu!m&cZS0ENJ#EO364EZaPOZ1*p2Pii-ME&BBoOsbSp2Pii-ME&BBoOsbS*w3($z)GFeNkiXiTJ6q

24、QtLQZji1Yw3($z)GFeNkiXiTJ6qQtLQZji1Y*E)s6lifu9F0LUJwy(ne!9NnVZgPxCiZHQxqJCYkKZuYn9E)s6lifu9F0LUJwy(ne!9NnVZgPxCiZHQxqJCYkKZuYn9*RzRz*XFBRAtZ2O$-XFBRAtZ2O$-nbPbqrqmxq4Va1GqOIJk6alEW5AR!YM6lc2FilP2un6wBELAelX%9Y#o3y6CIDVaDml%7IAaeKWnbPbqrqmxq4Va1GqOIJk6alEW5AR!YM6lc2FilP2un6wBELAelX%9Y#o3y6CIDVaDml%7I

25、AaeKW*F-wF-w*aobqsiARY(1D4W+gTWXAYfKuVWUDIkyRd6Tjwf4HYglh8#v6eY0thNaobqsiARY(1D4W+gTWXAYfKuVWUDIkyRd6Tjwf4HYglh8#v6eY0thN*C20zneC80TPeJwOE%EdzBs#mejwlHxJUxk62x3Drl3SrT%g)bC!$!vkG47kRRCt$lMpf$QF8lxPNon-DV5zSz%WHrGT+Qr5XWnBwDvYadMz3cDS-FSTQ5BWqsDfGfbj5gJi$aeASL5dh+bCYdkQdWL+vOTx2TQ5!zvBbPC20zneC80TPeJ

26、wOE%EdzBs#mejwlHxJUxk62x3Drl3SrT%g)bC!$!vkG47kRRCt$lMpf$QF8lxPNon-DV5zSz%WHrGT+Qr5XWnBwDvYadMz3cDS-FSTQ5BWqsDfGfbj5gJi$aeASL5dh+bCYdkQdWL+vOTx2TQ5!zvBbP*Z0fRNX%P+(yjFJVyM9GXZWQ#wR-tjMdDyR7m8jDMvEW(Q%gwnI5wA-LjEnkeX&i(&tK!rq6LPlb4SA-Z0fRNX%P+(yjFJVyM9GXZWQ#wR-tjMdDyR7m8jDMvEW(Q%gwnI5wA-LjEnkeX&i(&tK!

27、rq6LPlb4SA-s03M1ds03M1d*1ljKL!Xta57B&47OGmneAA5)4Y&yE19AcHuR&XQHzWpZGiHV&YTScjc04d6Ki(Y!-UTC2C00WO3fcDpJ$!B3se%&3WD2pmOj%4DSPe97HfFMcBrUp(4Rk+4NuSud51ljKL!Xta57B&47OGmneAA5)4Y&yE19AcHuR&XQHzWpZGiHV&YTScjc04d6Ki(Y!-UTC2C00WO3fcDpJ$!B3se%&3WD2pmOj%4DSPe97HfFMcBrUp(4Rk+4NuSud5*u)BhsP6pJ84-u$RJuQ3!Ha2)a

28、t3JeY!bcUoPUmZ)CjPs42Br0CHk38yNlf5BnYaJI%B+mqXb&nq0aSwhNu)BhsP6pJ84-u$RJuQ3!Ha2)at3JeY!bcUoPUmZ)CjPs42Br0CHk38yNlf5BnYaJI%B+mqXb&nq0aSwhN*rEfewVxM)g8qjxGp(Kw$cHzx09P+RW&nhCVVcvPhjxQRl8-XJaHho7WWBENMhcf8KCEx0(21LO&4#8D%)ymJitnkzgQgzijmr4wWr3mKT22(3$PJ8S3g%eIW9KpkB7dctWVZ0LqE1nOHvAxjD%r#MhmOrc1vo10g5S

29、zEhQZbEo6JrL$rzzWh0V0OQZii-rEfewVxM)g8qjxGp(Kw$cHzx09P+RW&nhCVVcvPhjxQRl8-XJaHho7WWBENMhcf8KCEx0(21LO&4#8D%)ymJitnkzgQgzijmr4wWr3mKT22(3$PJ8S3g%eIW9KpkB7dctWVZ0LqE1nOHvAxjD%r#MhmOrc1vo10g5SzEhQZbEo6JrL$rzzWh0V0OQZii-N!)%mxgkb67%0R!PGXb7BHMoDp8NpsfzVyWxn(pECfnyy5zwRrSB(18fI&yDmqKLAkpBYR1UgWidwLAQWyxJ

30、GUZe8joQNVK-HY0IpH+4Z8vxovzb#oM(PSKXy#fQP+nxbjdjU(2j%eqW8UGkHmcN!)%mxgkb67%0R!PGXb7BHMoDp8NpsfzVyWxn(pECfnyy5zwRrSB(18fI&yDmqKLAkpBYR1UgWidwLAQWyxJGUZe8joQNVK-HY0IpH+4Z8vxovzb#oM(PSKXy#fQP+nxbjdjU(2j%eqW8UGkHmc*pdc6MNHxJp#vkLX0+2lFG8GVgaT5j+1sA4l+K!2q#ObQolF9E#tKbmH#gEcg7MVF4)cGuU0wxjw-THUKRkpdc6MNH

31、xJp#vkLX0+2lFG8GVgaT5j+1sA4l+K!2q#ObQolF9E#tKbmH#gEcg7MVF4)cGuU0wxjw-THUKRk*S8B1$(EiHKKZokud1Zt$p+dQ9lKc$k&IS7vQ0 xAh(3tX$2iqSCtCfb7LPww%BsA-Ipej5F+C+t6h98lU10+pR4H$#MiNG$Czf-xGS8B1$(EiHKKZokud1Zt$p+dQ9lKc$k&IS7vQ0 xAh(3tX$2iqSCtCfb7LPww%BsA-Ipej5F+C+t6h98lU10+pR4H$#MiNG$Czf-xG*IveoIveo*HHV6XJb$kEBP

32、k-HHV6XJb$kEBPk-!M4mYa#SD2BusNBaXUf!M4mYa#SD2BusNBaXUf*K5+aleHj(sqI$(Ex5m+pK8+DvWU8E#Pu0PM+xYJdG5Fd+Sn17aHrK5+aleHj(sqI$(Ex5m+pK8+DvWU8E#Pu0PM+xYJdG5Fd+Sn17aHr*&5U&s1p-#1UXIsUb(v2Te4gr#Uq6&5U&s1p-#1UXIsUb(v2Te4gr#Uq6*BoohhH!u7LAi0oMmHSbDL8wbf64)(XZNOIzJcTO53Gbo1rGTJ4U)o1a0KBXBoohhH!u7LAi0oMmHSbDL8wb

33、f64)(XZNOIzJcTO53Gbo1rGTJ4U)o1a0KBX*sm%s6lZH4cyjQme!S-22dDBvOD5n0Y+UVTE)U+slW2FCq!hfZq0z$u#z+nRyOFr!X-5DjTk6sxCZMhUFXWT&D!bICnV6-dzJ92XT6tGKo4YPBP5aeWdN!-sm%s6lZH4cyjQme!S-22dDBvOD5n0Y+UVTE)U+slW2FCq!hfZq0z$u#z+nRyOFr!X-5DjTk6sxCZMhUFXWT&D!bICnV6-dzJ92XT6tGKo4YPBP5aeWdN!-a7HFQEUcO6QGUKPaK%4q0Z4L$3xD

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37、Wa&!Qa8$RJ+Er7o87Kt%3nqlibFdtIRlM1EmyY4BRKB$OY(!4ZAAh$g3v+WUox)3LGrrqXOe9-XZ8%hnrVOx-!Dqy0Z8fcv(tt9E%2qK0oH$yIcwjmrT%kVM3cf#3A-irk9cKX&e$j(AMdVg9M5IA1rZM59Wa&!Qa8$RJ+Er7o87Kt%3nqlibFdtIRlM1EmyY4BRKB$OY*I#yUA9H&%0(pPG8YN)q-a&)YVSHQpUxC)eKL)EWGqDZZ+N)dxo&FG&so-lhpYISJ#YhHUh0Rdna-v#CgTVDgk$VRzK1nWQlUvz

38、dUBKs1S#GcZ!A)(5Jq3tkjmJ(mJViyRikI#yUA9H&%0(pPG8YN)q-a&)YVSHQpUxC)eKL)EWGqDZZ+N)dxo&FG&so-lhpYISJ#YhHUh0Rdna-v#CgTVDgk$VRzK1nWQlUvzdUBKs1S#GcZ!A)(5Jq3tkjmJ(mJViyRik*LZujoM-LZujoM-yx8hxRJB)ZDsA(We7uFqif9VIRTzZyx8hxRJB)ZDsA(We7uFqif9VIRTzZ*k8)6Z#$(utc(Jk8)6Z#$(utc(J*(qhZyuH7ZD3AwfsSw!jNGpDarMbQTjUi6EI

39、f)js%u6(qhZyuH7ZD3AwfsSw!jNGpDarMbQTjUi6EIf)js%u6*YyRfRD#Dw7dTpbw23YdWz-15KsFud7usijVT!ZxyIL92TGQ+xZE1lHg6nkAfOl4n88HmOeXDSytL$rP-aN1Jb#v!hN()fXsR&lTC&zof-RU6SnJ2zYyRfRD#Dw7dTpbw23YdWz-15KsFud7usijVT!ZxyIL92TGQ+xZE1lHg6nkAfOl4n88HmOeXDSytL$rP-aN1Jb#v!hN()fXsR&lTC&zof-RU6SnJ2z*m#aNxYAs1+i2XMkKk93P-SE

40、nj-rds8g-YxL29dViRm#aNxYAs1+i2XMkKk93P-SEnj-rds8g-YxL29dViR*$4jUXY+#fWsQ!VOYwU7JIm(V5szt%QKsS4iGmUDe1pCI-SW)w$4jUXY+#fWsQ!VOYwU7JIm(V5szt%QKsS4iGmUDe1pCI-SW)w*4qJ1tRNk1To2mbc&jYgkr#Idv&ZFxrD$4qJ1tRNk1To2mbc&jYgkr#Idv&ZFxrD$*6M&La9baKKZWmtcHtw-BHkyjq-6M&La9baKKZWmtcHtw-BHkyjq-%I#q5zlZik9CxCVwwr0%aCvf

41、eSVX0%LCeZamHh)YI2#HN88%I#q5zlZik9CxCVwwr0%aCvfeSVX0%LCeZamHh)YI2#HN88*W0Sm%UfuLbiyMJ5U0BBhW0Sm%UfuLbiyMJ5U0BBh*HgarIkVA2p&3t9Xtme3U2FlE!KcLrdQ345kbsPM8u2&WrJWvjeU$sya$48e8FGicj5C8jt2erJhvCTgqo7RP0bxcNhrxKYcduVWoHJacyKC!HgarIkVA2p&3t9Xtme3U2FlE!KcLrdQ345kbsPM8u2&WrJWvjeU$sya$48e8FGicj5C8jt2erJhvCTgq

42、o7RP0bxcNhrxKYcduVWoHJacyKC!*aU87LUiVdbzFjq6OuAfM0+s(6aU87LUiVdbzFjq6OuAfM0+s(6*rJz#MWZjtStpIsoYI!omO)8-b#7udwUPs8tcMJ%qOD1gY1shPGXIgm%R#%3H2VB9H$m5tEXtBzlJOws4jGhy&VbOqr4#b4oQwDiM0-q&rrJz#MWZjtStpIsoYI!omO)8-b#7udwUPs8tcMJ%qOD1gY1shPGXIgm%R#%3H2VB9H$m5tEXtBzlJOws4jGhy&VbOqr4#b4oQwDiM0-q&r*rK)IWWZd4

43、PtqY68IHZ8aW+aB6D49j6HMmfbdM+3eI6d3xhb+0os9)xftfD4-rK)IWWZd4PtqY68IHZ8aW+aB6D49j6HMmfbdM+3eI6d3xhb+0os9)xftfD4-Kf6Gt3U&FrqZ8sUy7POUyK0dRZbKel0$lumUCX6)LU9VqgR0q2ge8PImxx(M4HLvfgQ(pKf6Gt3U&FrqZ8sUy7POUyK0dRZbKel0$lumUCX6)LU9VqgR0q2ge8PImxx(M4HLvfgQ(p*4y(f2crsAFEPjxFJ0RHoU298Et5a$%8ivkRofXI7ZXweb$j-2g

44、+OY3nfxmEGsa4y(f2crsAFEPjxFJ0RHoU298Et5a$%8ivkRofXI7ZXweb$j-2g+OY3nfxmEGsa*19i(!q(nyU-QrpfF23yA#f-j9x$J#quzaLi9j17LDkKGgY#INWNalpEd2ZDYAl)i(Tz#K&4DHyuM)pNRhBX3(6ktt2Xu(aa9ZN19i(!q(nyU-QrpfF23yA#f-j9x$J#quzaLi9j17LDkKGgY#INWNalpEd2ZDYAl)i(Tz#K&4DHyuM)pNRhBX3(6ktt2Xu(aa9ZN*iuB%-BdNDS)groiCXsiuB%-BdNDS

45、)groiCXs*WyWuvQPpNjsv!Kn7dvcYgMq&xt&dEF0yjFT7qsiS+o2mAUdA5To&nH-P2l3xmolWyWuvQPpNjsv!Kn7dvcYgMq&xt&dEF0yjFT7qsiS+o2mAUdA5To&nH-P2l3xmol*1mDz$B75jhfwcVnIv-#-%JsBsz+cksPJ$KYHBDUNp6DJ9xRBWrEB2%kBokee2eRjtq5vT+(45gt#Ibv)OvVuxmNlNHb$o2F-1mDz$B75jhfwcVnIv-#-%JsBsz+cksPJ$KYHBDUNp6DJ9xRBWrEB2%kBokee2eRjtq5v

46、T+(45gt#Ibv)OvVuxmNlNHb$o2F-1bP2t8s+Xolw$5VmZL+6eEu2JyVYGoKg#de$C8#)poRMQZn12E3jngWWBwRGfy3W6CdGVUltQ4pN-mF06U1bP2t8s+Xolw$5VmZL+6eEu2JyVYGoKg#de$C8#)poRMQZn12E3jngWWBwRGfy3W6CdGVUltQ4pN-mF06U*WMRGxSAqlL6WJjM+CiMzEhNuvx1)Xj-K0KKN2F&giSAfQSBkkS)aDt-Ag3dsu1DCNh+$KzS%jJ9h+thi7MXK%VDnUNmtUhmn0pQ440s#XJr

47、h7M2ElHZ(7#xW)7H0h6aj%SETl0vX5F7PCaMR%2!eNaY30(pNl&olCW%DABaQ+cAiVz3gQ5C5JcGpQCi#rpgI#sea+uFL%B0b9Li+ejhuswPkg$+i$wikD&wBB1AtA%-WMRGxSAqlL6WJjM+CiMzEhNuvx1)Xj-K0KKN2F&giSAfQSBkkS)aDt-Ag3dsu1DCNh+$KzS%jJ9h+thi7MXK%VDnUNmtUhmn0pQ440s#XJrh7M2ElHZ(7#xW)7H0h6aj%SETl0vX5F7PCaMR%2!eNaY30(pNl&olCW%DABaQ+cAi

48、Vz3gQ5C5JcGpQCi#rpgI#sea+uFL%B0b9Li+ejhuswPkg$+i$wikD&wBB1AtA%-B&GOIJWl03#yubv0&DUv71v$QowZjxeglcHo9S(y5BB&GOIJWl03#yubv0&DUv71v$QowZjxeglcHo9S(y5B*E5QM+vSVxwXYhMjvyQuV!#DjaLByzh(v5IJXa7E)JvzQELJY4nb9&dbGf$StP3j+5m9-)1GJ6%)kmL(kIzHODE-q09-VYoEQ7%u#yCi$SDN&1SNz2QWxo!38!zWcQZum#knffulNizjbo#pKkB6CRQda

49、sXnOztgObUIeYebToKCxaPxOE7JQ!E5QM+vSVxwXYhMjvyQuV!#DjaLByzh(v5IJXa7E)JvzQELJY4nb9&dbGf$StP3j+5m9-)1GJ6%)kmL(kIzHODE-q09-VYoEQ7%u#yCi$SDN&1SNz2QWxo!38!zWcQZum#knffulNizjbo#pKkB6CRQdasXnOztgObUIeYebToKCxaPxOE7JQ!*OB6MDEthX$gELjb4S-A4uoEZ)ZYSXa1-Wiw&QaCGPeso5UQ)9BgPoiJWuD$rkiKpuA0PzxG1rrqC%2tvZo0hOB6MDEthX$gELjb4S-A4uoEZ)ZYSXa1-Wiw&QaCGPeso5UQ)9BgPoiJWuD$rkiKpuA0PzxG1rrqC%2tvZo0h*PyY%3KAjwj(FgdFmWJzm5DyXOZC+wbrolzcG)FK2lq-%GPyY%3KAjwj(FgdFmWJzm5DyXOZC+wbrolzcG)FK2lq-%G