AGuIX, a theranostic nanoparticle to improve image-guided radiation therapy : a proof ofconcept in pancreatic cancer
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(8) _öbmKö am#bi MiB2H GǶQ#D2+iB7 T`BM+BT H /2 H ` /BQi?û` TB2 2bi /2 /ûi`mB`2 H2b +2HHmH2b + M+û`2mb2b iQmi 2M T`ûb2`p Mi H2b iBbbmb b BMbX lM2 m;K2Mi iBQM HQ+ H2 /2 H /Qb2 /ûHBp`û2 T ` ` /BQi?û` TB2 2bi +2T2M/ Mi Mû+2bb B`2 TQm` +2`i BM2b imK2m`b ` /BQ`ûbBbi Mi2b +QKK2 +2HH2 /m T M+`û bX lM2 i2HH2 bBim iBQM /2K M/2 HQ`b /2 i`Qmp2` mM +QKT`QKBb 2Mi`2 H /Qb2 /2 ` /B iBQM /ûHBp` #H2 ¨ H imK2m` 2i +2HH2 `2Ïm2 T ` H2b +2H@ HmH2b b BM2b pQBbBM Mi2b /2 K MBĕ`2 ¨ M2 T b /ûT bb2` H2m` b2mBH /2 iQHû` M+2X G2b +HBMB[m2b miBHBb2Mi ¨ HǶ?2m`2 +im2HH2 /2b Kûi?Q/2b /2 ` /BQi?û` TB2 /2 T`û+BbBQM +QKK2 H ` /BQi?û` TB2 +QM7Q`K iBQMM2HH2 T ` KQ/mH iBQM /ǶBMi2MbBiû U_*JAV +QKT`2M Mi H2b Kûi?Q/2b /ǶB`` /B iBQM bi2T M/ b?QQi 2i BMi2MbBiv KQ/mH i2/ `+ i?2` Tv UoJhV- 2i / Mb mM2 KQBM/`2 K2bm`2 H T`QiQMi?û` TB2- H ? /`QMi?û` TB2 Qm /2b B`` /B iBQMb bvM+?`Qi`QMbX .2b Kûi?Q/2b Hi2`M iBp2b bQMi +2T2M/ Mi T`QTQbû2b TQm` m;K2Mi2` H2 +QMi`ƬH2 HQ+ H /2 H ` /BQi?û` TB2- +QKK2 HǶmiBHBb iBQM /Ƕ ;2Mib ` /BQb2MbB#BHBb MibX HǶQTTQbû /2b ;2Mib +?BKB[m2b ` /BQb2MbB#BHBb Mib +QKK2 H hB` T x KBM2 Qm H *`Q+ûiBM2- MQmb pQMb miBHBbû mM2 M MQT `iB+mH2 +QKT`2M Mi /2b ûHûK2Mib /2 ? mi MmKû`Q iQKB[m2 U2X;X- H2 ; /QHBM@ BmKV / Mb H2 #mi /Ƕ KTHB}2` HQ+ H2K2Mi HǶ2z2i i?û` T2miB[m2 /2 H ` /BQi?û` TB2X .2 T `i H2m` MmKû`Q iQKB[m2- +2b iQK2b #ûMû}+B2Mi /ǶmM2 7Q`i2 + T +Biû /Ƕ #bQ`TiBQM T ` 2z2i T?QiQûH2+i`B[m2 /2b T?Q@ iQMb /2 7 B#H2 ûM2`;B2 UIRyy F2oV }M /2 ;ûMû`2` mM /ûTƬi HQ+ H /2 /Qb2 T ` HǶûKBbbBQM /2 T?QiQûH2+@ i`QMb 2i /ǶûH2+i`QMb m;2`X 1M THmb /2 +`û2` mM 2z2i T?vbB[m2- HǶ +iBp iBQM /2 H M MQT `iB+mH2 T ` H2b T?QiQMb BM+B/2Mib +`û2 /2b bm#bi M+2b +?BKB[m2b +QMi`B#m Mi ¨ H 7Q`K iBQM /2 HûbBQMb bBKTH2b 2i /Qm#H2 #`BMb /2 HǶ.L- K Bb T2`K2i û; H2K2Mi /Ƕ2M/QKK ;2` H K2K#` M2 +2HHmH B`2 2i +2`i BMb Q`; MBi2b /m +viQTH bK2 +QM/mBb Mi ¨ H KQ`i +2HHmH B`2X *2ii2 TT`Q+?2 K2Mû m /ûp2HQTT2K2Mi /2 MQK#`2mb2b M MQT `iB+mH2b +QKK2 +2HH2b ¨ # b2 /Ƕ `;2Mi Uw49dV- ; /QHBMBmK Uw4e9V- ? 7MBmK Uw4dkV- Q` Uw4dNV- 2i #BbKmi? Uw439VX HǶ?2m`2 +im2HH2- H2 +QmTH ;2 b+ MQ;` T?B2 Ĝ A_J 2bi +Qm` KK2Mi miBHBbû TQm` H /ûHBMû iBQM imKQ` H2 /2b iBbbmb KQmb UT`Qbi i2- imK2m`b +û`û#` H2b- T M+`û bVX .2 MQK#`2mt /ûp2HQTT2K2Mib bǶQ`B2Mi2Mi p2`b H +QM+2TiBQM /2 K +?BM2b +QmTH Mi mM2 A_J ¨ HǶ ++ûHû` i2m` HBMû B`2 ¨ H TH +2 /2b BK ;2m`b 2K# `[mûb bm` H2b ++ûHû` i2m`b HBMû B`2b U*"*hV TQm` ;mB/2` H2b i` Bi2K2Mib 2M i2KTb `û2H2i BMbB #ûMû}+B2` /ǶmM2 K2BHH2m`2 [m HBiû /2 pBbm HBb iBQM /2b iBbbmb KQmb ;`+2 ¨ HǶA_JX G2b M MQT `iB+mH2b +QKT`2M Mi /m ; /QHBMBmK bQMi T `iB+mHBĕ`2K2Mi / Tiû2b TQm` mM2 miBHBb iBQM 2M +HBMB[m2X 1HH2b TQbbĕ/2Mi /2b T`QT`Bûiûb K ;MûiB[m2b ii` v Mi2b TQm` HǶA_J BMbB [m2 /2b T`Q@ T`Bûiûb /Ƕ ;2Mi ` /BQb2MbB#BHBb Mi TQm` H ` /BQi?û` TB2X . Mb +2 + /`2- MQi`2 û[mBT2 /ûp2HQTTû mM MQmp2 m ivT2 /2 M MQT `iB+mH2b ¨ # b2 /2 ; /QHBMBmK TQmp Mi āi`2 bmBpB2b T ` A_J T`ĕb BMD2+iBQM BMi` p2BM2mb2 2i b2`p Mi /Ƕ ;2Mib ` /BQb2MbB#BHBb Mib ¨ ? mi2 2{+ +Biû, H2b M MQT `iB+mH2b :mAsX *2b M MQT `iB+mH2b bQMi +QKTQbû2b /ǶmM +Q2m` /2 TQHvbBHQt M2 2MiQm`û /2 HB; M/b +v+HB[m2b /û`Bpûb /m .Ph U +B/2 R-9-d-Ry@iûi` @ x +v+HQ/Q/û+ M2 @ R-9-d-Ry@iûi` @ +ûiB[m2V ;`2zûb /2 K MBĕ`2 +Qp H2Mi2 ¨ H K i`B+2 /2 TQHvbBHQt M2X 1HH2b T`ûb2Mi2Mi mM /B Kĕi`2 ?v/`Q/vM KB[m2 /2 j ± R MK 2i mM2 K bb2 /Ƕ2MpB`QM Ry F. X " bû bm` HǶûim/2 /2b M MQT `iB+mH2b :mAs- +2ii2 i?ĕb2 T`ûb2Mi2 m b2BM /2 +2b j +? TBi`2b, RV mM2 ûp Hm iBQM M HviB[m2 /2 HǶBKTQ`i M+2 /m +?QBt /m 7 Bb+2 m /ǶB`` /B iBQM 2i /2 HǶBKT +i /2b /B7@ 7û`2Mib T ` Kĕi`2b /ǶB`` /B iBQM Ui BHH2 /2 +? KT /ǶB`` /B iBQM- T`Q7QM/2m` /ǶB`` /B iBQM- KQ/ HBiû /ǶB`` /B iBQM Ue Jo 2i e Jo@666V- kV mM2 ûp Hm iBQM BM pBi`Q TQm` +QKT `2` HǶ2{+ +Biû /m 7 Bb+2 m e Jo@666 T ` ` TTQ`i m 7 Bb+2 m +HBMB[m2 e Jo BMbB [mǶmM2 ûp Hm iBQM /2b T ` Kĕi`2b /ǶB`` /B iBQM /û+`Bib T`û+û/2KK2Mi- jV mM2 ûp Hm iBQM iQtB+QHQ;B[m2 T`ĕb BMD2+iBQM BMi` p2BM2mb2 /2b M MQT `iB+@ mH2b- H2m` T`QT`Bûiû /2 +QMi` bi2 A_J 2i /2 +B#H ;2 imKQ` H- 2i H2m` 2{+ +Biû ` /BQb2MbB#BHBb Mi2 p2+ B`` /B iBQM +HBMB[m2 e Jo 2i e Jo@666X. d.
(9) TT`Q+?2 M HviB[m2 G T`2KBĕ`2 T `iB2 /2 H i?ĕb2 TQm` #mi /Ƕûp Hm2` /2 K MBĕ`2 M HviB[m2 HǶ2{+ +Biû /2b M MQT `@ iB+mH2b /m` Mi mM2 B`` /B iBQM +HBMB[m2 2i /ǶQTiBKBb2` H2b T ` Kĕi`2b /ǶB`` /B iBQMb T?vbB[m2b TQm` bbm`2` mM2 2{+ +Biû QTiBK H2 /2b M MQT `iB+mH2bX GǶ p Mi ;2 /m + H+mH M HviB[m2 T ` ` TTQ`i m + H+mH JQMi2@* `HQ 2bi b ` TB/Biû /Ƕ2tû+miBQMX "B2M [m2 KQBMb T`û+Bb [m2 H2 + H+mH JQMi2@* `HQ- H2 + H+mH M HviB[m2 HǶ p Mi ;2 /ǶQz`B` 2M [m2H[m2b KBMmi2b mM2 B/û2 ` TB/2 /2 HǶBKT +i /2 H KQ/B}@ + iBQM /m T ` Kĕi`2 ûim/BûX Cmb[mǶ¨ T`ûb2Mi- TQm` Q#i2MB` mM K2BHH2m` 2z2i ` /BQb2MbB#BHBb Mi- H2 +? HH2M;2 ûi Bi /Ƕ m;K2Mi2` H +QM+2Mi` iBQM /2 M MQT `iB+mH2b / Mb H imK2m`- /2 /BKBMm2` H i BHH2 /2 H M MQT `iB+mH2- Qm /2 H KQ/B}2` +?BKB[m2K2Mi TQm` m;K2Mi2` bQM i2KTb /2 +B`+mH iBQM / Mb H2 b M;X . Mb MQi`2 ûim/2MQmb MQmb bQKK2b +QM+2Mi`ûb bm` H2b Kûi?Q/2b /ǶB`` /B iBQM [mB m;K2Mi2Mi HǶ2z2i #BQT?vbB[m2 /2b M MQT `iB+mH2bX AH 2bi +QMp2Mm [m2 HǶ m;K2Mi iBQM /2 T?QiQMb /2 7 B#H2 ûM2`;B2 UIk8y F2oV T2`K2i mM2 +iBp iBQM /2b M MQT `iB+mH2b T ` 2z2i T?QiQûH2+i`B[m2- K2M Mi ¨ /2b + b+ /2b /ǶûH2+i`QMb m;2` 2i ¨ H ;ûMû` iBQM /2 /û`Bpûb +iB7b /2 HǶQtv;ĕM2 U_PaVX *2 T?ûMQKĕM2 T2`K2i mt M MQT `iB+mH2b /Ƕāi`2 2{+ +2b p2+ /2b 7 Bb+2 mt /ǶB`` /B iBQM T`û+HBMB[m2 Ukky FoVX *2T2M/ Mi- H K DQ`Biû /2b T @ iB2Mib bQMi i` Biûb p2+ /2b B`` /B iBQMb /2 HǶQ`/`2 /m K2; @2H2+i`QMpQHi Ue Jo / Mb NyW /2b + bVX *2b 7 Bb+2 mt bQMi +QKTQbûb /ǶmM bT2+i`2 /ǶûM2`;B2 p2+ mM2 ûM2`;B2 KQv2MM2 /2 RXk8 J2o- 2i mM2 i`ĕb 7 B#H2 T `i /2 T?QiQMb # bb2 ûM2`;B2X LQmb pQMb BMbB ûp Hmû HǶ2z2i /2 H T`Q7QM/2m` /ǶB`` /B iBQM- /2 H i BHH2 /2 +? KT- K Bb û; H2K2Mi HǶBKT +i /m 7 Bb+2 m /ǶB`` /B iBQM bm` H +`û iBQM /ǶmM /Qm+Bbb2K2Mi /2 7 Bb+2 m U/BKBMm2` HǶûM2`;B2 KQv2MM2 /m bT2+i`2 /ǶûM2`;B2 TQm` m;K2Mi2` H2b T?QiQMb /2 7 B#H2 ûM2`;B2VX lM2 7QBb H2b T ` Kĕi`2b p HB/ûb- MQmb pQMb +QKT `û /Bzû`2Mib 7 Bb+2 mt /ǶB`` /B iBQM +HBMB[m2 TQm` +iBp2` :mAsX LQmb pQMb +QKT `û HǶ2{+ +Biû i?ûQ`B[m2 /ǶmM 7 Bb+2 m e Jo p2+ mM 7 Bb+2 m e Jo@666 2bb2MiB2HH2K2Mi miBHBbû 2M ` /B iBQM biû`ûQi tB[m2 2i +QMMm TQm` b + T +Biû ¨ m;K2Mi2` H2b ûH2+i`QMb /2 +QMi KBM @ iBQMX 1M}M- MQmb pQMb 2z2+imû mM + H+mH T`2M Mi 2M +QKTi2 H KQ/B}+ iBQM /2 H +B#H2 T2`K2ii Mi /2 ;ûMû`2` H2b T?QiQMbX :ûMû` H2K2Mi- +2ii2 +B#H2 2bi +QKTQbû2 /2 +mBp`2fimM;biĕM2X LQmb pQMb T`QTQbû /2 H `2KTH +2` T ` mM2 +B#H2 /2 + `#QM2 [mB T2`K2i mM2 m;K2Mi iBQM /2 H ;ûMû` iBQM /2 T?QiQMb /2 7 B#H2 ûM2`;B2 p2+ mM2 ûM2`;B2 K tBKmK /2 kX8 J2oX GǶ2Mb2K#H2 /2b `ûbmHi ib Q#i2Mmb +QM}`K2 [m2 HǶ /Qm+Bbb2K2Mi /2 7 Bb+2 m T2`K2i /Ƕ m;K2Mi2` HǶ2z2i /2 /Qb2 BM/mBi T ` H2b M MQT `iB+mH2b :mAsX *2T2M/ Mi- TQm` /2 7 B#H2b i BHH2b /2 +? KT UI j+K t j+KV- +2 T?ûMQKĕM2 MǶ2bi THmb Q#b2`pûX 1M 2z2i- mM T?ûMQKĕM2 /2 /m`+Bbb2K2Mi /2 7 Bb+2 m U #bQ`TiBQM /2b T?QiQMb /2 7 B#H2 ûM2`;B2 2i m;K2Mi iBQM /2 HǶûM2`;B2 KQv2MM2 /m bT2+i`2 /ǶûM2`;B2V 2bi Q#b2`pû / Mb H2b T`Q7QM/2m`b ûim/Bû2b U= Ry +KV- K2M Mi ¨ mM2 /BKBMmiBQM /2 HǶ2z2i /2b M MQT `iB+mH2bX 1M}M- ¨ T ` Kĕi`2b /ǶB`` /B iBQMb B/2MiB[m2b- mM2 m;K2Mi iBQM /2 HǶ2z2i ` /BQb2MbB@ #BHBb Mi /2 ky@j8W 2bi ii2M/m2 p2+ HǶmiBHBb iBQM /m 7 Bb+2 m e Jo@666 +QKT `û m 7 Bb+2 m e JoX G KQ/B}+ iBQM i?ûQ`B[m2 /2 H +B#H2 +mBp`2fimM;bi2M2 T ` /m +mBp`2 T2`K2ii` Bi [m Mi ¨ 2HH2 mM2 m;K2Mi iBQM /2 THmb /ǶmM 7 +i2m` Ry /2 HǶ2z2i /2b M MQT `iB+mH2b T ` ` TTQ`i m 7 Bb+2 m e Jo@666X *2b `ûbmHi ib 2M+Qm` ;2 Mib QMi /QMMû HB2m ¨ mM2 BMp2biB; iBQM T`û+HBMB[m2 TQm` p HB/2` H2b `ûbmHi ib M HviB[m2b p2+ / Mb mM T`2KB2` i2KTb mM2 ûp Hm iBQM BM pBi`Q- TmBb BM pBpQX. :mAs- mM ;2Mi ` /BQb2MbB#BHBb Mi 277B+ +2, T`2mp2 /2 +QM@ +2Ti BM pBi`Q G2b i2bib BM pBi`Q MQmb QMi T2`KBb /Ƕûp Hm2` 2i /2 +QKT `2` HǶ2{+ +Biû /2b M MQT `iB+mH2b :mAs p2+ B`` /B iBQMb T`û+HBMB[m2b Ukky FoV 2i +HBMB[m2b Ue Jo- e Jo@666V K Bb û; H2K2Mi /2 [m MiB}2` HǶBKT +i /2 HǶBMi2`M HBb iBQM /2b M MQT `iB+mH2b bm` H2m` 2{+ +Biû ` /BQb2MbB#BHBb Mi2X G2b M MQT `iB+@ mH2b :mAs ûi Mi T`BM+BT H2K2Mi +QMbiBimû2b /Ƕ iQK2b /2 ; /QHBMBmK- H2m` BMi2`M HBb iBQM m b2BM /2b +2HHmH2b T M+`û iB[m2b bǶ2bi [m MiB}û2 T ` A_J 2i H2b `ûbmHi ib Q#i2Mmb QMi 2MbmBi2 ûiû +QKT `ûb mt. 3.
(10) `ûbmHi ib A*S@JaX LQmb pQMb Q#b2`pû [mǶ T`ĕb R? 2MpB`QM- H +2HHmH2 2bi b im`û2 /Ƕ:mAs p2+ mM2 +QM+2Mi` iBQM /2 HǶQ`/`2 /2 R-8 T;f+2HHmH2 /2 ; /QHBMBmKX m b2BM KāK2 /2 H +2HHmH2- H2b M MQT `iB+@ mH2b bQMi +QM+2Mi`û2b bQmb H 7Q`K2 /2 +Hmbi2` /2 M MQT `iB+mH2bX LQmb pQMb ûp Hmû HǶ2{+ +Biû /2b M MQT `iB+mH2b :mAs / Mb H2b +QM/BiBQMb QTiBK H2b /ǶB`` /B iBQM, R? /ǶBM+m# iBQM 2i B`` /B iBQM T`û+HBMB[m2 Ukky FoVX LQmb Q#b2`pQMb mM2 m;K2Mi iBQM bB;MB}+ iBp2 /2b + bbm`2b /Ƕ.L /Qm#H2 #`BMb- mM2 m;K2Mi iBQM /2 KQ`i TQTiQiB[m2- 2i mM2 /BKBMmiBQM bB;MB}+ iBp2 /2 H pB2 +2HHmH B`2 bm` H2 HQM; i2`K2 ûp Hmû2 T ` 2bb B +HQMQ;ûMB[m2 / Mb H +QM/BiBQM /2 i` Bi2K2Mi :mAs Y B`` /B iBQM T`û+HBMB[m2X T`ĕb pQB` +QM}`Kû HǶ2{+ +Biû /2b M MQT `iB+mH2b :mAs TQm` mM2 HB;Mû2 +2HHmH B`2 T M+`û iB[m2 + T M@R- MQmb pQMb ûp Hmû HǶBKT +i /2b T ` Kĕi`2b /ǶB`` /B iBQMb +HBMB[m2b bm` HǶ2{+ +Biû /2 H M MQT `iB+mH2X LQmb pQMb /ûKQMi`û HǶBM~m2M+2 /2 HǶ /Qm+Bbb2K2Mi /m 7 Bb+2 m +HBMB[m2 bm` HǶ m;K2Mi iBQM /2 HǶ2{+ +Biû /2b M MQT `iB+mH2b- K Bb û; H2K2Mi +QM}`Kû HǶ m;K2Mi iBQM /2 H KQ`i +2HHmH B`2 HQ`b[m2 :mAs 2bi +QmTHû2 ¨ HǶB`` /B iBQM e Jo@666X LQmb pQMb /ûKQMi`û HQ`b /2 +2b B`` /B iBQMb BM pBi`Q [m2 HǶmiBHBb iBQM /2b :mAs T2`K2i mM2 2b+ H /2 /2 /Qb2 KāK2 HQ`b[m2 +2HH2b@+B M2 bQMi T b BMi2`M HBbû2b / Mb H +2HHmH2- +QM}`K Mi H2b /B7@ 7û`2Mi2b ?vTQi?ĕb2b /Ƕ2z2ib #BQHQ;B[m2b i2H [m2 H +`û iBQM /2 /û`Bpûb +iB7b /2 HǶQtv;ĕM2X *2b `ûbmHi ib MQmb QMi T2`KBb /Ƕ p M+2` ¨ HǶûi T2 BM pBpQ Qɍ MQmb pQMb `û HBbû mM2 ûim/2 /2 iQt@ B+QHQ;B2 bm` bQm`Bb BMbB [mǶmM2 ûp Hm iBQM /2 HǶ2{+ +Biû /2b M MQT `iB+mH2b :mAs p2+ B`` /B iBQM T`û+HBMB[m2 2i +HBMB[m2 T`ĕb H2m` BMD2+iBQM BMi` p2BM2mb2X. :mAs- mM2 M MQT `iB+mH2 i?ö` MQbiB[m2 TQm` H ` /BQi?ö` TB2 ;mB/ö2 T ` HǰBK ;2 T`ĕb H T`2mp2 `û HBbû2 BM pBi`Q- MQmb MQmb bQKK2b T2M+?ûb bm` HǶûim/2 /Ƕ:mAs BM pBpQX :`+2 ¨ HǶ2z2i i?û` MQbiB[m2 /2b M MQT `iB+mH2b Ui?û` T2miB[m2 2i /B ;MQbiB[m2V- MQmb pQMb Tm ûp Hm2` H2m` #BQ/Bbi`B#miBQM T ` A_JX .2 T `i H2m` /B Kĕi`2 ?v/`Q/vM KB[m2 UBM7û`B2m` ¨ 8 MKV- H2b M MQT `iB+@ mH2b :mAs QMi +B#Hû MQi`2 KQ/ĕH2 bQmb@+mi Mû /2 imK2m` T M+`û iB[m2 / Mb H2b jy KBMmi2b T`ĕb BMD2+iBQM p Mi /2 bǶûHBKBM2` b Mb iQtB+Biû Qm 2z2ib b2+QM/ B`2b T ` H2b `2BMbX *2ii2 ûim/2 /2 #BQ/Bbi`B@ #miBQM ûiû p HB/û2 T ` A*S@Ja [mB 2bi +QMbB/û`û +QKK2 H2 ;QH/ bi M/ `/ TQm` K2bm`2` H [m MiBiû /2 Kûi H / Mb mM Q`; M2X *2ii2 ûim/2 /2 #BQ/Bbi`B#miBQM MQmb T2`KBb /2 /ûi2`KBM2` H2 KQK2Mi T`QTB+2 TQm` bbm`2` [m2 HǶB`` /B iBQM bQBi `û HBbû2 m KQK2Mi Qɍ H2 THmb ;` M/ MQK#`2 /2 M MQT `iB+mH2b bQB2Mi T`ûb2Mi2b / Mb H imK2m`X LQmb pQMb BMbB [m MiB}û HǶ2z2i /2b M MQT `iB+mH2b / Mb j +QM/BiBQMb /BbiBM+i2b /ǶB`` /B iBQM, mM2 B`` /B iBQM T`û+HBMB[m2 c mM2 B`` /B iBQM e Jo +HBMB[m2 c mM2 B`` /B iBQM e Jo@666 +HBMB[m2X *? +mM /2 +2b i` Bi2K2Mib ûiû `û HBbû p2+ mM2 B`` /B iBQM mMB[m2 /2 Ry :vX GǶB`` /B iBQM T`û+HBMB[m2 bǶ2bi /û`QmHû2 p2+ k 7 Bb+2 mt Q`i?Q;QM mt Uy 2i Ny /2;`ûbV i M/Bb [m2 H2b B`` /B iBQMb +HBMB[m2b QMi ûiû `û HBbû2b p2+ mM b2mH 7 Bb+2 m ¨ R3y /2;`ûbX . Mb H2 + b /2b B`` /B iBQMb +HBMB[m2b- H bQm`Bb 2bi TH +û2 2M TQbBiBQM p2Mi` H2 bm` Ry +K /2 bQHB/2 /2 /2MbBiû û[mBp H2Mi2 ¨ HǶ2 m USJJV p2+ k +K /2 #QHmb bm` H2 /Qb TQm` +Qmp`B` H imK2m`X SQm` +? [m2 ûim/2 `û HBbû2- mM 2z2i bB;MB}+ iB7 ûiû Q#b2`pû T ` ` TTQ`i ¨ HǶB`` /B iBQM +QMi`ƬH2 /2 Ry :v p2+ mM2 m;K2Mi iBQM /2 H bm`pB2 /2 THmb /2 88 DQm`b TQm` H2 7 Bb+2 m T`û+HBMB[m2- 98 DQm`b TQm` H2 e Jo 2i ek DQm`b TQm` H2 e Jo@666X m+mM2 iQtB+Biû /B`2+i2K2Mi HBû2 ¨ H T`ûb2M+2 /2b M MQT `iB+mH2b / Mb H2b Q`; M2b b BMb MǶ ûiû Q#b2`pû2X *2b ûim/2b BM pBpQ QMi T2`KBb /2 +QM}`K2` H MQM@iQtB+Biû /2b :mAs 2i H2m` 2{+ +Biû /ǶmiBHBb iBQM +QKK2 ;2Mi /B ;MQbiB[m2- H2m` MQM@BMi2` +iBQM /m` Mi HǶB`` /B iBQM / Mb H2b iBbbmb b BMb- 2i H2m` 2{@ + +Biû p2+ /2b 7 Bb+2 mt /ǶB`` /B iBQM +HBMB[m2X. *QM+HmbBQM 1M THmb /2b T ` Kĕi`2b /ǶB`` /B iBQM- /Ƕ mi`2b 7 +i2m`b +HBMB[m2b z2+i2Mi û; H2K2Mi HǶBKT +i /2b. N.
(11) M MQT `iB+mH2b bm` HǶ m;K2Mi iBQM /2 H /Qb2 HQ+ H2X G p b+mH `Bb iBQM /2 H imK2m`- b T2`Kû #BHBiû2i /Ƕ mi`2b 7 +i2m`b #BQHQ;B[m2b BKT +i2Mi HǶBMi2`M HBb iBQM- H #BQ/Bbi`B#miBQM- 2i HǶ2{+ +Biû i?û` T2m@ iB[m2 /2b M MQT `iB+mH2bX G HQ+ HBb iBQM /2 H imK2m`- b pBbB#BHBiû T ` H2b KQ/ HBiûb /ǶBK ;2`B2bH2 bmBpB /2 bQM KQmp2K2Mi +`ûû T ` H `2bTB` iBQM /m T iB2Mi- BMbB [m2 /Ƕ mi`2b T?ûMQKĕM2b T?vb@ BQHQ;B[m2b bQMi /2b +? HH2M;2b +Qm` KK2Mi `2M+QMi`ûb 2M +HBMB[m2X GǶmiBHBb iBQM /2 T`Q/mBib /2 +QM@ i` bi2 v Mi /2b + ` +iû`BbiB[m2b bBKBH B`2b ¨ +2HH2b /2 H M MQT `iB+mH2 :mAs T2`K2i /Ƕ /`2bb2` +2b +? HH2M;2bX GǶmiBHBb iBQM T`û@i` Bi2K2Mi 2i /m` Mi H2 i` Bi2K2Mi /2 HǶA_J 2M ` /BQi?û` TB2 `2T`ûb2Mi2Mi /2 MQmp2HH2b KQ/ HBiûb 2M +HBMB[m2 BM/B[m Mi mM #2bQBM BKTQ`i Mi /Ƕ ;2Mib b2`p Mi ¨ H 7QBb /2 T`Q/mBi /2 +QMi` bi2 2i /2 ` /BQb2MbB#BHBb MiX G M MQT `iB+mH2 :mAs `ûTQM/ ¨ +2 #2bQBM 2M T2`K2ii Mi mM2 K2BHH2m`2 T`û+BbBQM /2 H ` /BQi?û` TB2 2M +QM/BiBQM +HBMB[m2 iQmi 2M m;K2Mi Mi bQM 2{+ +BiûX GǶ2{+ +Biû /2b :mAs ¨ H 7QBb +QKK2 ;2Mi /B ;MQbiB[m2 2i i?û` T2miB[m2 ûiû /ûKQMi`û¨ H bmBi2 /ǶmM2 BMD2+iBQM BMi` p2BM2mb2 /2 7 B#H2 +QM+2Mi` iBQM bm` mM KQ/ĕH2 bQmb@+mi Mû /Ƕ /ûMQ+ `+BMQK2 T M+`û iB[m2X :`+2 m Kû+ MBbK2 /Ƕ +iBp iBQM /2b M MQT `iB+mH2b- H2b `ûbmHi ib Q#i2Mmb T2mp2Mi āi`2 ûi2M/mb ¨ iQmi mi`2 KQ/2H imKQ` H +Q``2+i2K2Mi p b+mH `Bbû / Mb H2 #mi /2 T2`K2ii`2 HǶ ++mKmH iBQM /2b :mAs T ` 2z2i T bbB7 / Mb H imK2m`X GǶmiBHBb iBQM /ǶmM2 K +?BM2 /2 ivT2 ~ ii2MBM; }Hi2` 7`22 T2`K2i mM2 m;K2Mi iBQM bB;MB}+ iBp2 /2 HǶ KTHB}+ iBQM /2 /Qb2 BM/mBi2 T ` H2b M MQT `iB+mH2b :mAs iQmi 2M /BKBMm Mi H2b /m`û2b /ǶB`` /B iBQM /m T iB2MiX lM i` Bi2K2Mi THmb T`û+Bb 2bi BMbB Q#i2Mm TQm` /2b bBi2b KQ#BH2b +QKK2 H2 T M+`û b Qm H2 TQmKQMX JāK2 p2+ mM B`` /B i2m` +HBMB[m2 bi M/ `/- +2 T?ûMQKĕM2 /Ƕ +iBp iBQM `2bi2 bB;MB}+ iB7 +QKT `û ¨ mM2 B`` /B iBQM bBKTH2X GǶ2Mb2K#H2 /2 +2b `ûbmHi ib T2`K2i /2 +QM}`K2` HǶ2{+ +Biû /2 +2ii2 M MQT `iB+mH2 / Mb /2b +QM/BiBQMb /ǶB`` /B iBQMb +HBMB[m2bX. Ry.
(12) *QMi2Mib R AMi`Q/m+iBQM RXR. RXk. RXj. RX9. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. Rd Rd RN RN ky kR k9 k9 k9 k8 k8. JQiBp iBQMb X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X "2 K KQ/2HBM; M/ /Qb2 /2TQbBiBQM + H+mH iBQM X X X X X X X X X X X X X kXkXR JQMi2@* `HQ bBKmH iBQM X X X X X X X X X X X X X X X X X X X X X X kXkXk M HviB+ H + H+mH iBQM X X X X X X X X X X X X X X X X X X X X X X X kXkXj S`Q# #BHBiv Q7 T?QiQM@M MQT `iB+H2 BMi2` +iBQM X X X X X X X X X AKT +i Q7 i?2 +HBMB+ H b2imT QM M MQT `iB+H2 +iBp iBQM X X X X X X X X X kXjXR .2Ti? M/ }2H/ bBx2 /2T2M/2M+v X X X X X X X X X X X X X X X X X kXjXk AKT +i Q7 i?2 ` /B iBQM #2 K 7Q` ` /B iBQM /Qb2 2M? M+2K2Mi *QM+HmbBQM X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Sm#HB+ iBQMb X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. kN kN jy jy jy jk jj jj j9 j8 je. X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. 9N 9N 8y 8y 8y 8k 8k 89 8e 8e. X X X X X X X. ed ed e3 e3 e3 eN dy dy. ai i2 Q7 `i X X X X X X X X X X X X X X X X RXRXR SQbBiBQMBM; Q7 i?2 i?2bBb X X X X RXRXk S`2b2Mi iBQM Q7 i?2 M MQT `iB+H2 PM /2K M/ M MQT `iB+H2 +iBp iBQM X X X RXkXR S?vbB+ H +iBp iBQM X X X X X X X RXkXk "BQHQ;B+ H `2 +iBQM X X X X X X X * M+2` bBi2 i `;2iBM; T`Q+2bb2b X X X X X RXjXR S bbBp2 i `;2iBM; X X X X X X X X RXjXk +iBp2 i `;2iBM; X X X X X X X X X Sm#HB+ iBQM X X X X X X X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. X X X X X X X X X X. k M HviB+ H TT`Q +? kXR kXk. kXj. kX9 kX8. j :mAs- M 2772+iBp2 ` /BQb2MbBiBx2` , BM pBi`Q T`QQ7 Q7 +QM+2Ti jXR jXk. jXj. jX9 jX8. JQiBp iBQMb X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X L MQT `iB+H2 mTi F2 #v +2HHb X X X X X X X X X X X X X X X X X X X X jXkXR J_A [m MiB}+ iBQM X X X X X X X X X X X X X X X X X X X X X jXkXk AM/m+iBp2Hv +QmTH2/ TH bK K bb bT2+i`QK2i`v p HB/ iBQM AM pBi`Q T`QQ7 Q7 +QM+2Ti X X X X X X X X X X X X X X X X X X X X X X X jXjXR S`QQ7 Q7 +QM+2Ti rBi? T`2+HBMB+ H ` /B iBQM #2 K X X X X X jXjXk S`QQ7 Q7 +QM+2Ti rBi? +HBMB+ H ` /B iBQM #2 K X X X X X X X *QM+HmbBQM X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Sm#HB+ iBQM X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. X X X X X X X X X. 9 h?2` MQbiB+ M MQT `iB+H2b 7Q` BK ;2@;mB/2/ ` /B iBQM i?2` Tv 9XR 9Xk 9Xj. 9X9. JQiBp iBQMb X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X MBK H KQ/2H X X X X X X X X X X X X X X X X X X X X X X X X X X X X X S? `K +QFBM2iB+b M/ #BQ/Bbi`B#miBQM bim/B2b X X X X X X X X X X X X 9XjXR "BQ/Bbi`B#miBQM BM KB+2 X X X X X X X X X X X X X X X X X X X X 9XjXk G b2` AM/m+2/ "`2 F/QrM aT2+i`Qb+QTv UGA"aV BK ;BM; X X LQM@?mK M T`BK i2b, #BQ/Bbi`B#miBQM M/ T? `K +QFBM2iB+b bim/v 9X9XR "BQ/Bbi`B#miBQM bim/v BM MQM@?mK M T`BK i2b X X X X X X X. RR. X X X X X X X. X X X X X X X. X X X X X X X. X X X X X X X. X X X X X X X. X X X X X X X. X X X X X X X. X X X X X X X. X X X X X X X.
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(18) 1. AMi`Q/m+iBQM *QMi2Mib RXR. RXk. RXj. RX9. ai i2 Q7 `i X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Rd RXRXR. SQbBiBQMBM; Q7 i?2 i?2bBb X X X X X X X X X X X X X X X X X X X X X X X. RN. RXRXk. S`2b2Mi iBQM Q7 i?2 M MQT `iB+H2 X X X X X X X X X X X X X X X X X X X. RN. PM /2K M/ M MQT `iB+H2 +iBp iBQM X X X X X X X X X X X X X X X X X X X X X ky RXkXR. S?vbB+ H +iBp iBQM X X X X X X X X X X X X X X X X X X X X X X X X X X. kR. RXkXk. "BQHQ;B+ H `2 +iBQM X X X X X X X X X X X X X X X X X X X X X X X X X X. k9. * M+2` bBi2 i `;2iBM; T`Q+2bb2b X X X X X X X X X X X X X X X X X X X X X X X k9 RXjXR. S bbBp2 i `;2iBM; X X X X X X X X X X X X X X X X X X X X X X X X X X X. k9. RXjXk. +iBp2 i `;2iBM; X X X X X X X X X X X X X X X X X X X X X X X X X X X X. k8. Sm#HB+ iBQM X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X k8. RXR ai i2 Q7 `i q?BH2 ` /B iBQM Bb 2z2+iBp2 BM FBHHBM; + M+2` +2HHb- i?2 /Qb2 b 72Hv /2HBp2` #H2 iQ i?2 i `;2i pQHmK2 Bb Q7i2M HBKBi2/ #v i?2 TQbbB#BHBiv Q7 +QHH i2` H / K ;2b iQ bm``QmM/BM; ?2 Hi?v iBbbm2bX >Qr2p2`- 7Q` bQK2 + M+2` bBi2b- Bi ? b #22M b?QrM i? i /Qb2 2b+ H iBQM BM i?2 imKQ` +QmH/ bB;MB}+ MiHv BKT`Qp2 HQ+ H +QMi`QH M/ T iB2Mi bm`pBp H (R)X q?BH2 `2+2MiHv /2p2HQT2/ K2i?Q/b bm+? b BMi2MbBiv@KQ/mH i2/ ` /B iBQM i?2` Tv UAJ_hV- pQHmK2i`B+ KQ/mH i2/ `+ i?2` Tv UoJhV- M/ BK ;2@;mB/2/ ` /B iBQM i?2` Tv UA:_hV ? p2 BKT`Qp2/ i?2 /2HBp2`2/ ` /B iBQM /Qb2 +QM7Q`K HBiv- /Qb2 2b+ H iBQM `2K BMb M BKTQ`i Mi +HBMB+ H +? HH2M;2 i? i M22/b iQ #2 //`2bb2/ iQ BKT`Qp2 i?2 2{+ +v Q7 ` /B iBQM i?2` Tv (k)X L MQT `iB+H2b /2bB;M Bb `BbBM; H M/b+ T2 BM i?2 2` Q7 KQ/2`M QM+QHQ;v Qz2`BM; M2r T2`bT2+iBp2b b b?QrM #v i?2 BM+`2 b2 Q7 b+B2MiB}+ Tm#HB+ iBQMb `2H i2/ iQ i?2B` mb2 BM ` /B iBQM QM+QHQ;v U6B;X RXRVX h?2 2M? M+2K2Mi Q7 ` /B iBQM 2z2+i BM/m+2/ #v ` /BQb2MbBiBxBM; M MQT `iB+H2b Bb T`Q# #Hv QM2 Q7 i?2 KQbi i` MbH iBQM H bT2+ibX _ /BQb2MbBiBxBM; M MQT `iB+H2b BM+`2 b2 i?2 ` /BQ#BQHQ;B+ H 2z2+ib rBi?BM i?2 bBi2 Q7 /Bb2 b2 r?BH2 K BMi BMBM; i?2 +m``2Mi +HBMB+ H +QMbi` BMib QM /Qb2 /2HBp2`2/ iQ ?2 Hi?v Q`; MbX h?2 T?QiQ2H2+i`B+ BMi2` +iBQM BM+`2 b2b bi`QM;Hv b 7mM+iBQM Q7 i?2 iQKB+ MmK#2` Q7 i?2 M MQT `iB+H2 UT`QTQ`iBQM H iQ ; − ; V- ;BpBM; i?2b2 T `iB+H2b ?B;? BMi2` +iBQM T`Q# #BHBiv. Rd.
(19) 6B;m`2 RXR, LmK#2` Q7 Tm#HB+ iBQMb `2H i2/ iQ i?2 mb2 Q7 M MQT `iB+H2b BM #BQHQ;v U/ `FV M/ ` /B iBQM QM+QHQ;v U;`2vV #2ir22M RNNd M/ kyRj (j)X. rBi? HQr 2M2`;v T?QiQMb M/ HHQrBM; i?2 7Q`K iBQM Q7 //BiBQM H /Bzmb2/ T?QiQMb- T?QiQ2H2+i`QMbm;2` 2H2+i`QMb M/ `2 +iBp2 Qtv;2M bT2+B2b U_PaV i? i ? p2 i?2 TQi2MiB H iQ KTHB7v i?2 #BQHQ;B+ H / K ;2X 1p2M mM/2` ?B;?@2M2`;v T?QiQM B`` /B iBQM- ?B;?@w M MQT `iB+H2b + M BMi2` +i rBi? T`BK `v Q` b2+QM/ `v bT2+B2b T2`KBiiBM; ?B;?Hv 2{+B2Mi M MQb+ H2 /Qb2 /2TQbBiBQM `QmM/ i?2 M MQT `iB+H2b (9)X *QMb2[m2MiHv- i?2 /Bz2`2MiB H 2z2+i #2ir22M ?2 Hi?v iBbbm2 M/ imKQ` iBbbm2 Bb BKT`Qp2/X h?2 2{+ +v Q7 M MQT `iB+H2b b ` /BQb2MbBiBx2`b ? b #22M /2KQMbi` i2/ i i?2 T`2+HBMB+ H H2p2H 7Q` KmHiBTH2 ?B;?@w M MQT `iB+H2b bBM+2 > BM72H/ 2i HX /2KQMbi` i2/ i?2 TQi2MiB H Q7 ;QH/ M MQT `iB+H2b 7i2` bvbi2KB+ BMD2+iBQM (8)- M/ i i?2 +HBMB+ H H2p2H 7Q` ? 7MBmK M MQT `iB+H2b (e)X >Qr2p2`- #2+ mb2 Q7 i?2 BMD2+iBQM K2i?Q/ UBMi` imKQ` H BMD2+iBQMV M/ #2+ mb2 Q7 i?2B` bBx2 U8y MKV- i?2 ? 7MBmK M MQT `iB+H2b TTHB+ iBQMb `2 K BMHv HBKBi2/ iQ 2 bv@iQ@ ++2bb imKQ` bBi2b- bm+? b b `+QK - ?2 / M/ M2+F- M/ T`Qbi i2 + M+2`bX 6Q` i?2 K DQ`Biv Q7 Qi?2` + M+2` bBi2b- BMi` p2MQmb BMD2+iBQM `2K BMb M Q#HB; iBQM M/ /Q2b MQi KQ/B7v i?2 bi M/ `/ +HBMB+ H T` +iB+2bX hQ //`2bb i?2b2 HBKBi iBQMb r?BH2 biBHH 2Mbm`BM; HQr iQtB+Biv iQ i?2 ?2 Hi?v iBbbm2b- i?2` MQbiB+ M MQT `iB+H2b r2`2 +`2 i2/- +QK#BMBM; /B ;MQbiB+ M/ i?2` T2miB+ T`QT2`iB2bX : /QHBMBmK Bb r2HH@FMQrM 2H2K2Mi 7Q` #BQK2/B+ H TTHB+ iBQMbX Aib mb2 BM K2/B+BM2 Bb /B`2+iHv +Q``2H i2/ rBi? i?2 /2p2HQTK2Mi Q7 +QMi` bi ;2Mib 7Q` J_A- MQM@BMp bBp2 M/ MQM@BQMBxBM; K2i?Q/ 7Q` +[mB`BM; pQHmK2i`B+ BK ;2b rBi? ?B;? bT iB H `2bQHmiBQM M/ 2t+2HH2Mi bQ7i@iBbbm2 +QMi` biX aQK2 +HBMB+b ? p2 #2;mM iQ `2TH +2 *h bBKmH iBQM rBi? J_A bBKmH iBQM 7Q` ` /B iBQM i`2 iK2Mi TH MMBM; Tm`TQb2b- M/ 7mim`2 J_@GAL* M/ J_@# b2/ `2 H@iBK2 imKQ` i` +FBM; i2+?MB[m2b `2 mM/2` /2@ p2HQTK2Mi (d- 3)X "2bB/2b i?2B` mb2 7Q` BK ;BM; TTHB+ iBQMb- ; /QHBMBmK # b2/ +QKTQmM/b `2 HbQ 2MpBb ;2/ 7Q` i?2` T2miB+ TTHB+ iBQMbX : /QHBMBmK /BbTH vb ?B;? + Tim`2 +`Qbb@b2+iBQM /m2 iQ Bib `2H iBp2Hv ?B;? iQKB+ MmK#2` Uw 4 e9V M/ + M BMi2` +i rBi? ?B;? 2M2`;B2b B`` /B iBQMb- K FBM; ; /QHBMBmK@# b2/ M MQT `iB+H2b 2z2+iBp2 ` /BQb2MbBiBx2`bX :mAs U+iBp iBQM M/ :mB/ M+2 Q7 A`` /B iBQM #v s@` vV Bb bm#@8MK M MQT `iB+H2 # b2/ QM TQHvbBHQt M2 M2irQ`F bm``QmM/2/ #v ; /QHBMBmK +?2H i2b /2bB;M2/ iQ #2 M 2z2+iBp2 J_A +QMi` bi ;2Mi M/ ` /BQb2MbBiBx2` (N- Ry)X "2+ mb2 Q7 i?2 p b+mH ` 2M/Qi?2HB H ;`Qri? 7 +iQ` Uo1:6V T`Q/m+2/ #v imKQ` +2HHb iQ biBKmH i2 i?2 imKQ` M;BQ;2M2bBb M/ Q7 i?2 H +F Q7 2z2+iBp2 HvKT? iB+ /` BM ;2 BM i?2 imKQ` iBbbm2b- :mAs + M T2M2i` i2 i?2 imKQ` 7i2` bvbi2KB+ BMD2+iBQM i? MFb iQ i?2 2M? M+2/ T2`K2 #BHBiv M/ `2i2MiBQM U1S_@V 2z2+iX h?2 M MQT `iB+H2 bi v BMbB/2 i?2 imKQ` 7Q` bB;MB}+ Mi. R3.
(20) T2`BQ/ Q7 iBK2- r?BH2 i?2 M MQT `iB+H2b r?B+? `2 MQi mTi F2M #v i?2 imKQ` `2 +H2 `2/ #v i?2 FB/@ M2vb- pQB/BM; iQtB+Biv Bbbm2b #v HBKBiBM; i?2 M MQT `iB+H2b 2tTQbBiBQM iQ ?2 Hi?v Q`; MbX S`2+HBMB+ H bim/B2b +QM/m+i2/ BM p `BQmb imKQ` KQ/2Hb ? p2 /2KQMbi` i2/ i? i HQr +QM+2Mi` iBQMb Q7 M MQT `iB@ +H2b BMD2+i2/ BMi` p2MQmbHv r2`2 ii` +iBp2 ` /BQb2MbBiBx2`b rBi? bB;MB}+ Mi i?2` T2miB+ 2z2+i- r?BH2 +QM}`KBM; i? i i?2 M MQT `iB+H2 Bb MQM@iQtB+ (RR)X AM //BiBQM- i?2 ?B;? HQM;Bim/BM H `2H tBpBiv Q7 :mAs URRXN±R b− XKJ− T2` :/ i ey J>xV HHQrb 7Q` #2ii2` +QMi` bi T`QT2`iB2b i? M +m``2Mi 6.@ TT`Qp2/ ; /QHBMBmK +?2H i2b- +`2 iBM; TQi2MiB H 7Q` 7mim`2 mb2 BM J_@;mB/2/ ` /B iBQM i?2`@ Tv- MQi #Hv rBi? i?2 mT+QKBM; J_@GAL* i2+?MQHQ;v (Rk- Rj)X h?2 HQ;B+ H bi2T 7i2` /2KQMbi` iBM; i?2 TQi2MiB H Q7 i?2 :mAs i i?2 T`2+HBMB+ H H2p2H 7Q` b2p2` H imKQ` HQ+ HBx iBQMb Bb iQ +QMiBMm2 i?2 M MQT `iB+H2 /2p2HQTK2Mi iQ i?2 +HBMB+ H bi2TX +m``2Mi ;QQ/ K Mm7 +im`BM; T` +iB+2 U+:JSV T`Q+2bb ? b #22M /2p2HQT2/ M/ i?2 `2;mH iQ`v iQtB+Biv i2bib QM irQ MBK H KQ/2Hb U`Q/2Mib M/ KQMF2vbV ? p2 b?QrM MQ 2pB/2M+2 Q7 iQtB+BivX *m``2MiHv- i?2 M MQT `iB+H2 :mAs ? b #22M p HB/ i2/ #v i?2 ;2M+2 L iBQM H2 /2 H a Miû 2i /m Jû/B+ K2Mi ULaJV iQ bi `i +HBMB+ H T? b2 A i`B H QM #` BM K2i bi bBb i i?2 :`2MQ#H2 >QbTBi H U6` M+2VX +HBMB+ H T? b2 A rBHH #2 T2`7Q`K2/ #v Qm` ;`QmT BM +HQb2 +QHH #Q` iBQM rBi? L> h?2`;mBt aa BM Q`/2` iQ V /2i2`KBM2 i?2 b 72iv Q7 i?2 M MQT `iB+H2 M/ Bib K tBKmK iQH2` i2/ /Qb2 BM T iB2Mib +QM+m``2MiHv i`2 i2/ rBi? bi M/ `/ +?2KQ` /B iBQMc #V /2}M2 i?2 `2+QKK2M/2/ T? b2 AA /Qb2 Q7 i?2 M MQT `iB+H2c M/ +V /2}M2 i?2 #BQ/Bbi`B#miBQM Q7 bBM;H2 BMi` p2MQmb BMD2+iBQM b r2HH b KmHiBTH2 BMD2+iBQMb BM Q`/2` iQ T`QpB/2 ` iBQM H2 Q7 /QbBM; /KBMBbi` iBQMX h?2b2 `2bmHib rBHH /2KQMbi` i2 i?2 i` MbH iBQM HHBiv Q7 mbBM; M MQT `iB+H2b b BK ;2@;mB/2/ ` /B iBQM i?2` Tv ;2MibX h?2 T`QQ7 Q7 +QM+2Ti Q7 mbBM; i?2 :mAs b i?2` MQbiB+ ;2Mi BM ?mK M rBHH #2 #`2 Fi?`Qm;? TT`Q +? 7Q` T iB2Mi #2M2}iX. RXRXR SQbBiBQMBM; Q7 i?2 i?2bBb h?Bb i?2bBb `2b2 `+? rQ`F ? b #22M +QKTH2i2/ i?`Qm;? T `iM2`b?BT #2ir22M i?2 AMbiBimi GmKBĕ`2@ J iBĕ`2- GvQM R U6` M+2V- bmT2`pBb2/ #v S`Q7X PHBpB2` hBHH2K2Mi- i?2 L MQ@_ /PM+ ;`QmT 7`QK i?2 /2T `iK2Mi Q7 _ /B iBQM PM+QHQ;v- . M @6 `#2` * M+2` AMbiBimi2 U.6*AV- "QbiQM J UlaV- bm@ T2`pBb2/ #v .`X _Qbb "2`#2+Q- bbQ+B i2 S`Q72bbQ` i i?2 > `p `/ J2/B+ H a+?QQH- M/ i?2 +QKT Mv L MQ@>- 6`2M+? +QKT Mv bT2+B HBx2/ BM /2bB;MBM; M MQT `iB+H2bX h?2 K BM ;Q H Q7 i?Bb i?2bBb Bb iQ /2KQMbi` i2 i? i i?2 mb2 Q7 :mAs M MQT `iB+H2b + M BKT`Qp2 i?2 i`2 iK2Mi Q7 T M+`2 iB+ + M+2` r?2M +QK#BM2/ iQ +HBMB+ H B`` /B iBQM- rBi?Qmi ? pBM; iQ KQ/B7v i?2 +m``2Mi +HBMB+ H rQ`F~QrX h?2 bvMi?2bBb Q7 i?2 :mAs M MQT `iB+H2b r b T2`7Q`K2/ BM i?2 AMbiBimi GmKBĕ`2 J iBĕ`2- r?BH2 i?2 T`QQ7 Q7 +QM+2Ti r b T2`7Q`K2/ i i?2 . M @6 `#2` * M+2` AMbiBimi2X. RXRXk S`2b2Mi iBQM Q7 i?2 M MQT `iB+H2 :mAs Bb bm#@8 MK M MQT `iB+H2 bvMi?2bBx2/ #v iQT@/QrM T`Q+2bb U6B;X RXkVX TQHvbBHQt M2 b?2HH Bb 7Q`K2/ `QmM/ i?2 H Mi? MB/2 +Q`2 M/ +?2H iBM; KQH2+mH2b U2X;X .PhV `2 ;` 7i2/ QM i?2 QmibB/2X lbBM; iQT@/QrM T`Q+2bb- i?2 H Mi? MB/2 QtB/2 +Q`2 Bb /BbbQHp2/ M/ i?2 :/+ `2 +?2H i2/ iQ 2KTiv .Ph bBi2b (R9)X h?2 `2bmHiBM; M MQT `iB+H2 U:/ aB * L P >Y V ? b TQHvbBHQt M2 +Q`2 bmTTQ`iBM; TT`QtBK i2Hv Ry +?2H iBM; bBi2b i? i 7Q` i?2 K DQ`Biv +QMi BM :/+ X h?2 `2K BMBM; .Ph + M #2 +?2H i2/ BM Q`/2` iQ ii +? S1h M/ aS1*h i` +2`b Q` +QK#BM iBQM i?2`2Q7- r?BH2 ~mQ`2b+2Mi T`Q#2b + M #2 ii +?2/ QM i?2 bm`7 +2 Q7 i?2 M MQT `iB+H2b- /2T2M/BM; QM i?2 /2bB`2/ TTHB+ iBQM U6B;X RXjV (R8)X h?Bb Q`B;BM H bi`m+im`2 2Mi` TTBM; i?2 7`22 ; /QHBMBmK iQKb BMiQ i?2 +?2H i2b HHQrb i?2 M MQT `iB+H2 iQ #2 MQMiQtB+ i ?B;? +QM+2Mi` iBQM- bi #H2 Qp2` iBK2- M/ +H2 `2/ i?`Qm;? i?2 FB/M2vb rBi?Qmi ++mKmH iBQM BM Qi?2` Q`; MbX AM i?Bb i?2bBb `2b2 `+? rQ`F- r2 mb2/ :mAs M MQT `iB+H2b +QKTQb2/ #v Ry +?2H i2b Q7 ; /QHBMBmK QMHvX lbBM; ; /QHBMBmK iQKb HHQrb i?2 M MQT `iB+H2b iQ +i b i?2` MQbiB+ ;2MiX. RN.
(21) 6B;m`2 RXk, a+?2K2 Q7 a_S bvMi?2bBb, V +Q`2 bvMi?2bBb- #V TQHvbBHQt M2 b?2HH bvMi?2bBb- +V .Ph: ;` 7iBM;/V i` Mb72` iQ r i2`- 2V +Q`2 /BbbQHmiBQM- 7V TQHvbBHQt M2 7` ;K2Mi iBQMX AK ;2 +Qm`i2bv Q7 JB;MQi 2i HX (Rj). 6B;m`2 RXj, h?2 :mAs + M #2 mb2/ b J_ +QMi` bi ;2Mi- M/ b ~mQ`2b+2Mi T`Q#2 Q` aS1*hfS1h i` +2`X. RXk PM /2K M/ M MQT `iB+H2 +iBp iBQM _ /BQb2MbBiBxBM; M MQT `iB+H2b K /2 Q7 ?B;?@w iQKb- bm+? b :mAs- ? p2 7Q` ;Q H iQ +`2 i2 /Bz2`2MiB H 2z2+i #2ir22M i?2 imKQ` M/ i?2 bm``QmM/BM; ?2 Hi?v Q`; MbX h?2 T`Q+2bb Q7 ?B;?@w M MQT `iB+H2b- bm+? b :mAs- Bb # b2/ QM T?vbB+ H BMi2` +iBQMb M/ #BQHQ;B+ H `2 +iBQMbX. ky.
(22) 6B;m`2 RX8, a+?2K iB+ `2T`2b2Mi iBQM Q7 i?2 S?QiQ2H2+i`B+ 2z2+i. RXkXR S?vbB+ H +iBp iBQM S?QiQMb + M BMi2` +i rBi? i?2 M MQT `iB+H2b pB #bQ`TiBQM- BM2H biB+ /BzmbBQM- Q` 2H biB+ /BzmbBQMX h?2b2 BMi2` +iBQMb K v ? TT2M rBi? i?2 2H2+i`QMb HQ+ HBx2/ `QmM/ i?2 Mm+H2mb- i?2 Mm+H2mb Bib2H7Q` i?2 2H2+i`QK ;M2iB+ }2H/ Q7 i?2 Mm+H2mbX q2 7Q+mb QM i?2 BMi2` +iBQMb `2H iBM; iQ i?2 ` /B iBQM i?2` Tv }2H/ TTHB2/ BM M MQK2/B+BM2, S?QiQ2H2+i`B+ 2z2+i M/ *QKTiQM 2z2+iX. S`2/QKBM2M+2 Q7 T?QiQM BMi2` +iBQMb h?2 /Bz2`2Mi BMi2` +iBQMb T`Q+2bb2b `2 /2i2`KBM2/ #v i?2 +`Qbb@b2+iBQM p Hm2X AM 7mM+iBQM Q7 i?2 2M@ 2`;v M/ i?2 iQKB+ MmK#2`- j bT2+B}+ `2;BQMb + M #2 Q#b2`p2/, GQr 2M2`;v f >B;? w, S?QiQ2H2+i`B+ 2z2+ic JQ/2` i2 2M2`;v f JQ/2` i2 w , *QKTiQM 2z2+i c >B;? 2M2`;v f >B;? w , S B` T`Q/m+iBQM U6B;X RX9VX. 6B;m`2 RX9, _2;BQMb r?2`2 QM2 Q7 i?2 i?`22 T?QiQM@K ii2` BMi2` +iBQMb /QKBM i2bX. S?QiQ2H2+i`B+ 2772+i AM T?QiQ2H2+i`B+ 2z2+i U6B;X RX8V- M BM+B/2Mi T?QiQM rBi? M 2M2`;v 2[m H iQ i?2 BMBiB H T?QiQM U?ɉ V `2H2 b2b i?2 iQi HBiv Q7 Bib 2M2`;v iQ M iQKB+ 2H2+i`QMX ". 9 + ɀ = F− +. ". 9+. URXRV. r?2`2 ɀ Bb i?2 BM+B/2Mi T?QiQM- s Bb i?2 iQK rBi? K bb - " 9+ Bb i?2 b K2 BQMBx2/ iQK- M/ F− Bb 7`22 2H2+i`QMX. kR.
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(26) 6B;m`2 RX3, a+?2K iB+ `2T`2b2Mi iBQM Q7 i?2 T bbBp2 i `;2iBM; T`Q+2bbX AK ;2 / Ti2/ 7`QK . M S22` 2i HX (ke). RXjXk +iBp2 i `;2iBM; h?2 +iBp2 i `;2iBM; Bb # b2/ QM i?2 BM+Q`TQ` iBQM Q7 bT2+B}+ ;2Mib rBi?BM i?2 M MQT`Q#2 7Q`KmH iBQMX >2M+2- MiB#Q/B2b- Ti K2`b- Q` T2TiB/2b `2 K BMHv mb2/ b i `;2iBM; HB; M/bX h?2b2 2MiBiB2b BK iQ bT2+B}+ HHv #BM/ iQ +2HH bm`7 +2b Q` KQH2+mH2b T`2b2Mi BM #mM/ Mi [m MiBiv i i?2 i `;2i bBi2- r?B+? BM + b2 Q7 imKQ`b ;2M2` HHv `272`b iQ `2+2TiQ`b Qp2`@2tT`2bb2/ 2Bi?2` #v i?2 + M+2` +2HHb i?2Kb2Hp2b Q` #v imKQ` 2M/Qi?2HB H +2HHbX h?2 2{+ +v Q7 M +iBp2 imKQ` i `;2iBM; M MQT `iB+H2 Bb BM KQbi Q7 i?2 + b2b BKT`Qp2/ #v i?2 #Qp2@K2MiBQM2/ 1S_@2z2+i (kd)X. RX9 Sm#HB+ iBQM. k8.
(27) SPECIAL FOCUS ❙ Nano-biomaterials at work: revolutionizing healthcare (Part I) Editorial For reprint orders, please contact: reprints@futuremedicine.com. Pushing radiation therapy limitations with theranostic nanoparticles “Nanoparticles design is a rising landscape in the era of modern oncology offering new perspectives.” First draft submitted: 2 March 2016; Accepted for publication: 10 March 2016; Published online: 13 April 2016 Keywords: CLINICAL TRIAL s GADOLINIUM s IMAGE GUIDED RADIATION THERAPY s RADIOSENSITIZER s THERANOSTIC NANOPARTICLES. In radiation oncology, while radiation is effective in killing cancer cells, the dose safely deliverable to the target volume is often limited by the possibility of collateral damage to surrounding healthy tissues. However, for some cancer sites, it has been shown that a dose escalation in the tumor could significantly improve local control and patient survival [1] . While recently developed methods such as intensity-modulated radiation therapy, volumetric-modulated arc therapy and imageguided radiation therapy have improved the delivered radiation dose conformality, dose escalation remains an important clinical challenge that needs to be addressed to improve the efficacy of radiation therapy [2] . Nanoparticles design is a rising landscape in the era of modern oncology offering new perspectives. The enhancement of radiation effect induced by radiosensitizing nanoparticles is probably one of the most translational aspects. Radiosensitizing nanoparticles increase the radiobiological effects within the site of disease while maintaining the current clinical constraints on dose delivered to healthy organs. The photoelectric interaction increases strongly as a function of the atomic number of the nanoparticle (proportional to Z4 –Z5), giving these particles a high interaction probability with low-energy photons and allowing the formation of additional diffused photons, photoelectrons, Auger electrons and reactive oxygen species that have the potential to amplify the biological damage. Even. 10.2217/nnm.16.38 © 2016 Future Medicine Ltd. under high-energy photon irradiation, highZ nanoparticles can interact with primary or secondary species permitting a highly efficient nanoscale dose deposition around the nanoparticle [3] . Consequently, the differential effect between healthy tissue and tumor tissue is improved. The efficacy of nanoparticles as radiosensitizers has been demonstrated at the preclinical level for multiple high-Z nanoparticles since Hainfeld et al. demonstrated the potential of gold nanoparticles after systemic injection [4] , and at the clinical level for hafnium nanoparticles [5] . However, because of the injection method (intratumoral injection) and because of their size (50 nm), the hafnium nanoparticle applications are mainly limited to easyto-access tumor sites, such as sarcoma, head and neck and prostate cancers. For the majority of other cancer sites, intravenous injection remains an obligation. To address these limitations while still ensuring low toxicity to the healthy tissues, theranostic nanoparticles were created, combining diagnostic and therapeutic properties. Gadolinium is the most well-known element for biomedical applications. Its use in medicine is directly correlated with the development of contrast agents for MRI, a noninvasive and nonionizing method for acquiring volumetric images with high spatial resolution and excellent soft-tissue contrast. Some clinics have begun to replace CT simulation with MRI simulation for radiation treatment. Nanomedicine (Lond.) (2016) 11(9), 997–999. ke. Alexandre Detappe )NSTITUT ,UMIERE -ATIERE
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(29) ,YON 5NIVERSITY
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(31) &RANCE AND $EPARTMENT OF 2ADIATION /NCOLOGY
(32) $ANA &ARBER #ANCER )NSTITUTE
(33) (ARVARD -EDICAL 3CHOOL
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(36) 53!. Francois Lux )NSTITUT ,UMIERE -ATIERE
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(40) &RANCE. Olivier Tillement !UTHOR FOR CORRESPONDENCE )NSTITUT ,UMIERE -ATIERE
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(42) ,YON 5NIVERSITY
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(44) &RANCE OLIVIERTILLEMENT UNIV LYONFR. part of. ISSN 1743-5889. 997.
(45) Editorial. Detappe, Lux & Tillement. planning purposes, and future MR-LINAC and MRbased real-time tumor tracking techniques are under development [6,7] . Besides their use for imaging applications, gadolinium-based compounds are also envisaged for therapeutic applications. Gadolinium displays high capture cross-section due to its relatively high atomic number (Z = 64) and can interact with high energies irradiations, making it an effective radiosensitizer.. “The enhancement of radiation effect induced by radiosensitizing nanoparticles is probably one of the most translational aspects.” Our group developed AGuIX (Activation and Guidance of irradiation by x-ray), a sub-5 nm nanoparticle based on a polysiloxane network surrounded by gadolinium chelates [8,9] , designed to be an effective MRI contrast agent and radiosensitizer. Because of the VEGF produced by tumor cells to stimulate the tumor angiogenesis and of the lack of effective lymphatic drainage in the tumor tissues, AGuIX can penetrate the tumor after a systemic injection thanks to the enhanced permeability and retention effect. The nanoparticles stay inside the tumor for a significant period of time, before being cleared by the kidneys, avoiding toxicity issues by limiting their exposition to healthy organs. Preclinical studies conducted in various tumor models have demonstrated that low concentrations of AGuIX injected intravenously were attractive radiosensitizers with a significant therapeutic effect, while confirming that the nanoparticle is nontoxic [10] . In addition, its high longitudinal relaxivity allows for better contrast properties than current US FDA-approved gadolinium chelates, creating a potential for future use in MRI-. References 1. 2. 3. 998. Budiharto T, Haustermans K, Van Cutsem E et al. A Phase I radiation dose-escalation study to determine the maximal dose of radiotherapy in combination with weekly gemcitabine in patients with locally advanced pancreatic adenocarcinoma. Radiat. Oncol. 3, 30 (2008). Jaffray DA. Image-guided radiotherapy: from current concept to future perspectives. Nat. Rev. Clin. Oncol. 9(12), 688–699 (2012). Mcquaid HN, Muir MF, Taggart LE et al. Imaging and radiation effects of gold nanoparticles in tumour cells. Sci. Rep. 6, 19442 (2016).. 4. Hainfeld JF, Slatkin DN, Smilowitz HM. The use of gold nanoparticles to enhance radiotherapy in mice. Phys. Med. Biol. 49(18), N309–N315 (2004).. 5. Min Y, Caster JM, Eblan MJ, Wang AZ. Clinical translation of nanomedicine. Chem. Rev. 115(19), 11147– 11190 (2015).. Nanomedicine (Lond.) (2016) 11(9). guiding radiation therapy, notably with the upcoming MR-LINAC technology [11,12] . The logical step after demonstrating the potential of AGuIX at the preclinical level for several tumor localizations is to continue the nanoparticles development to the clinical step. A current GMP manufacturing process has been developed and the regulatory toxicity tests on two animal models (rodents and monkeys) have shown no evidence of toxicity. A clinical Phase I will be investigated in France by our group in close collaboration with NH TherAguix SAS in order to determine the safety of AGuIX and its maximum tolerated dose in patients concurrently treated with standard chemoradiation; define the recommended phase II dose of AGuIX; and define the biodistribution of a single intravenous injection as well as multiple AGuIX injections in order to provide a rationale of AGuIX dosing administration. These results will demonstrate the translationality of using nanoparticles as image-guided radiation therapy agents and further clinical trial will be performed to quantify the therapeutic benefits of AGuIX. The proof-of-concept of using AGuIX as a theranostic agent in human will be a breakthrough approach for patient benefit. Financial & competing interests disclosure & ,UX
(46) AND / 4ILLEMENT HAVE ONE PATENT TO DISCLOSE 7/ 4HIS PATENT PROTECTS SOME OF THE NANOPAR TICLES DESCRIBED IN THIS PUBLICATION !'U)8 4HE AUTHORS HAVE NO OTHER RELEVANT AFlLIATIONS OR lNANCIAL INVOLVEMENT WITH ANY ORGANIZATION OR ENTITY WITH A lNANCIAL INTEREST IN OR lNANCIAL CONmICT WITH THE SUBJECT MATTER OR MATERIALS DISCUSSED IN THE MANUSCRIPT APART FROM THOSE DISCLOSED .O WRITING ASSISTANCE WAS UTILIZED IN THE PRODUCTION OF THIS MANUSCRIPT. 6. (P015) Radiation Biological Responses of MRI-Linac vs Linac in Human Head and Neck and Lung Cancer Cells. Oncology 29(4 Suppl. 1), pii:205024 (2015) (Epub ahead of print).. 7. Keall PJ, Barton M, Crozier S et al. The Australian magnetic resonance imaging-linac program. Semin. Radiat. Oncol. 24(3), 203–206 (2014).. 8. Sancey L, Lux F, Kotb S et al. The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy. Br. J. Radiol. 87(1041), 20140134 (2014).. 9. Lux F, Sancey L, Bianchi A et al. Gadoliniumbased nanoparticles for theranostic MRIradiosensitization. Nanomedicine (Lond.) 10(11), 1801–1815 (2015).. 10. Sancey L, Kotb S, Truillet C et al. Long-term in vivo clearance of gadolinium-based AGuIX nanoparticles and their biocompatibility after systemic injection. ACS Nano 9(3), 2477–2488 (2015).. future science group. kd.
(47) Pushing radiation therapy limitations with theranostic nanoparticles. 11. Detappe A, Kunjachan S, Rottmann J et al. AGuIX nanoparticles as a promising platform for image-guided radiation therapy. Cancer Nanotechnol. 6(1), 4 (2015).. 12. Editorial. Le Duc G, Miladi I, Alric C et al. Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles. ACS Nano 5(12), 9566–9574 (2011).. www.futuremedicine.com. future science group. k3. 999.
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(52) M/ _ Bb i?2 `2bB/m H ` M;2 Q7 i?2 T?QiQ2H2+i`QM i i?2 TQBMi `- rBi? 3 = 3UPU − S- rBi? 3UPU i?2 iQi H ` M;2 Q7 i?2 T?QiQ2H2+i`QM 7Q` M 2M2`;v 1, 3UPU = . (& + .). − .X h?2 #bQ`#2/ /Qb2 Bb /2}M2/ b i?2 2M2`;v /2TQbBi2/ BM i?2 2M/Qi?2HB H +2HH /BpB/2/ #v Bib K bbX h?Bb + H+mH iBQM /Q2b MQi +QMbB/2` /Qb2 iQ 2M/Qi?2HB H +2HHb 7`QK M MQT `iB+H2b HQ+ i2/ QM i?2 QTTQbBi2 bB/2 Q7 i?2 #HQQ/ p2bb2H Q` i?Qb2 +QMi BM2/ rBi?BM i?2 #HQQ/ p2bb2H U#mi MQi +HQb2 iQ i?2 r HHVX :Bp2M i?2 2M2`;v Q7 i?2 2KBii2/ T?QiQ2H2+i`QMb- i?2 //BiBQM H /Qb2 +QMi`B#miBQM 7`QK i?2 7Q`K2` b?QmH/ MQi #2 bB;MB}+ Mi #2+ mb2 r2 `2 bbmKBM; M +iBp2 i `;2iBM; K2i?Q/ M/ B`` /B iBQM i i?2 iBK2 TQBMi Q7 7mHH2bi `2i2MiBQM (jN)- r2 rBHH HbQ bbmK2 i? i MQ :mAs `2 biBHH ~QrBM; i?`Qm;? i?2 p2bb2Hb i i?2 iBK2 Q7 B`` /B iBQMX h?2 2M2`;v #BM rBi? i?2 H `;2bi +QMi`B#miBQM ? b K2 M p Hm2 Q7 NdX8 F2oX 6Q` i?Bb 2M2`;v #BM- i?2 T`Q# #BHBiv iQ +`2 i2 T?QiQ2H2+i`QM Bb 2[m H iQ eXRtRy− T2` T?QiQM BM+B/2Mi mTQM ; /QHBMBmK M MQT `iB+H2 rBi? 8 MK /B K2i2`X h?2 bBx2 Bb `#Bi` `BHv +?Qb2M 7Q` 2 b2 Q7 +QKT `BbQM rBi? i?2 2 `HB2` rQ`FX b BM i? i bim/v- i?2 M MQT `iB+H2 bBx2 2M/b mT + M+2HBM; Qmi r?2M i?2 Qp2` HH HQ+ H +QM+2Mi` iBQM Bb BMp2biB; i2/X h?2 //BiBQM H /Qb2 /2TQbBi2/ BMbB/2 i?2 /D +2Mi 2M/Qi?2HB H +2HH #v QM2 :mAs@T?QiQM BMi2` +iBQM i i?Bb 2M2`;v Bb jXjtRy− :vX. kXj AKT +i Q7 i?2 +HBMB+ H b2imT QM M MQT `iB+H2 +iBp iBQM kXjXR .2Ti? M/ 7B2H/ bBx2 /2T2M/2M+v qBi? HQ+ H +QM+2Mi` iBQM Q7 :mAs M MQT `iB+H2b 2[m H iQ jy K;fKH- ah. /2HBp2`v K2i?Q/- i k +K /2Ti?- 7Q` }2H/ bBx2 RytRy +K - i?2 2M/Qi?2HB H /Qb2 2M? M+2K2Mi 7 +iQ` U1.16V Bb 2[m H iQ RXe9 7Q` i?2 NdX8 F2o 2M2`;v #BMX h?Bb `2bmHi Bb bBKBH ` iQ Qm` T`2pBQmb bim/v mbBM; /Bz2`2Mi bQm`+2 7Q` i?2 T?QiQM 2M2`;v bT2+i` X amKKBM; HH Q7 i?2 2M2`;v #BMb 7Q` i?Bb b2i@mT- i?2 iQi H 1.16 Bb RXNX AM ;2M2` H- 1.16 BM+`2 b2b rBi? }2H/ bBx2- ;QBM; 7`QK RXk Ujtj +K - ah.- ky +K /2Ti?V iQ jX8 UR9tk3 +K - ah.- ky +K /2Ti?VX h?2 iQi H ` M;2 BM 1.16 + H+mH i2/ Bb 7`QK RXk Ujtj +K - ah.ky +K /2Ti?V iQ 9Xk UR9t k3 - 666- ky +K /2Ti?VX h?2 /Bz2`2M+2b BM 1.16 7Q` 2 +? +QM};m` iBQM + M #2 2tTH BM2/ #v i?2 2z2+ib Q7 }2H/ bBx2- /2Ti?- M/ /2HBp2`v KQ/2- QM i?2 bT2+i` H +QMi2Mi Q7 i?2 T?QiQM #2 K i i?2 TQBMi Q7 BMi2` +iBQMX 6Q` }2H/ bBx2b ;`2 i2` i? M 8t8 +K - 1.16 BM+`2 b2b rBi? BM+`2 bBM; /2Ti? 7Q` #Qi? ah. M/ 666 /2HBp2`B2bX 6Q` 8t8 +K M/ #2HQr- 1.16 Bb `Qm;?Hv +QMbi Mi rBi? /2Ti? 7Q` ah. /2HBp2`v M/ /2+`2 b2b bHB;?iHv rBi? /2Ti? 7Q` 666 /2HBp2`vX AM i?Bb bim/v- r2 ? p2 + H+mH i2/ i?2 /Qb2 2M? M+2K2Mi /m2 iQ T?QiQ2H2+i`B+ BMi2` +iBQMb QMHv2t+Hm/BM; i?2 +QMi`B#miBQMb Q7 m;2` 2H2+i`QMb b r2HH b *QKTiQM BMi2` +iBQMb U6B;X kX9VX m;2` T`Q/m+iBQM r b MQi BM+Hm/2/ #2+ mb2 Bi ? b #22M b?QrM i? i i?2 BKT +i Q7 m;2` 2H2+i`QMb Bb KQbi bm#bi MiB H #2HQr ky F2o BM+B/2Mi T?QiQMbX AM //BiBQM- i?2 p2`v b?Q`i ` M;2 Q7 m;2` 2H2+i`QMb M2+2bbBi i2b +HQb2 T`QtBKBiv Q7 i?2 bQm`+2 rBi? i?2 .L i `;2i- bQK2i?BM; r?B+? Bb MQi BM+Hm/2/ BM Qm` +QMb2`p iBp2 KQ/2HX h?2 +`Qbb@b2+iBQM 7Q` *QKTiQM BMi2` +iBQMb ? b HBiiH2 /2T2M/2M+2 QM i?2 iQKB+ MmK#2` UwV Q7 i?2 K i2`B H M/- i?2`27Q`2- Bb MQi 2tT2+i2/ iQ +QMi`B#mi2 bm#bi MiB HHv iQ i?2 1.16X Ai b?QmH/ #2 MQi2/- ?Qr2p2`- i? i B7 Qm` bbmKTiBQMb `2 BM+Q``2+i M/ m;2` M/ *QKTiQM BMi2` +iBQMb r2`2 H27i Qmi BM 2``Q`- i?Bb rQmH/ QMHv H2 / iQ H `;2` /Qb2 2M? M+2K2Mi i? M Bb `2TQ`i2/ ?2`2X h?2`27Q`2- Qm` `2bmHib + M #2 i F2M b +QMb2`p iBp2 2biBK i2 QM i?2b2 ;`QmM/bX Sm#HBb?2/ 2tT2`BK2Mi H `2bmHib BM +2HH +mHim`2 BM/B+ i2 bBKBH ` }M/BM;b H#2Bi rBi? H2bb 2M2`;v /2T2M/2M+2 i? M 2tT2+i2/X lbBM; }ii2/ HBM2 ` [m /` iB+ T ` K2i2`b- *?Bi?` MB 2i HX (9y) b?Qr2/ /Qb2 2M? M+2K2Mi 7 +iQ`b Q7 RXee URy8 FoTV- RX9j Ukky FoTV- RXR3 U *bV- M/ RXRd Ue JoVX C BM 2i HX (9R) 7QmM/ 7 +iQ`b Q7 RX9R URey FoTV- RXkN Ue JoV- M/ RXRe UR8 JoV 7Q` J.J"@kjR +2HHb M/ MQ bB;MB}+ Mi 2z2+i 7Q` GRjk Q` .lR98 +2HHbX aBKBH ` 2z2+ib r2`2 b22M #v GBm 2i HX (9k)- #mi i?2 Tm#HBb?2/ `2bmHib `2 MQi 2 bBHv +QKT ` #H2X q?BH2 bQK2 Q7 i?2b2 /Bz2`2M+2b K v #2 /m2 iQ M MQT `iB+H2 7Q`KmH iBQM- +2HH HBM22tT2`BK2Mi H b2imT- /Qb2 + H+mH iBQM- M/ Qi?2` 2tT2`BK2Mi H T`Q+2/m`2b- Bi Bb biBHH TQbbB#H2 i? i bQK2 Qi?2` 7 +iQ` Bb HBKBiBM; i?2 2{+ +v Q7 i?2 Fo #2 KbX aT2+mH iBQM QM i?Bb Bb #2vQM/ i?2 b+QT2 Q7 i?2 +m``2Mi rQ`F- #mi Bi Bb bQK2i?BM; i? i b?QmH/ #2 BMp2biB; i2/X. jj.
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