ab0e4ad7900183b5350ba591eac1b6f5 pmc_33066346.pdf 5d424f681b3301676dceb99687c64e4128f26b48 pmc_33066346.pdf 6bde0a0b0cc18aba91e5dcc9b9e7e9cdd17f5add196b612b1de46f45b26166f0 pmc_33066346.pdf Title: Proteomic Characterization of Urinary Extracellular Vesicles from Kidney-Transplanted Patients Treated with Calcineurin Inhibitors Subject: Use of immunosuppressive drugs is still unavoidable in kidney-transplanted patients. Since their discovery, calcineurin inhibitors (CNI) have been considered the first-line immunosuppressive agents, in spite of their known nephrotoxicity. Chronic CNI toxicity (CNIT) may lead to kidney fibrosis, a threatening scenario for graft survival. However, there is still controversy regarding CNIT diagnosis, monitoring and therapeutic management, and their specific effects at the molecular level are not fully known. Aiming to better characterize CNIT patients, in the present study, we collected urine from kidney-transplanted patients treated with CNI who (i) had a normal kidney function, (ii) suffered CNIT, or (iii) presented interstitial fibrosis and tubular atrophy (IFTA). Urinary extracellular vesicles (uEV) were enriched and the proteome was analyzed to get insight into changes happening during CNI. Members of the uroplakin and plakin families were significantly upregulated in the CNIT group, suggesting an important role in CNIT processes. Although biomarkers cannot be asserted from this single pilot study, our results evidence the potential of uEV as a source of non-invasive protein biomarkers for a better detection and monitoring of this renal alteration in kidney-transplanted patients. Keywords: exosomes; renal transplantation; tacrolimus; cyclosporine A; proteomics Author: Laura Carreras-Planella, Javier Juega, Omar Taco, Laura Cañas, Marcella Franquesa, Ricardo Lauzurica and Francesc Enric Borràs Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Wed Oct 14 07:07:08 2020 CEST ModDate: Wed Oct 14 07:07:08 2020 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3338874 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- UFOIXQ+URWPalladioL-Ital Type 1 Custom yes yes no 94 0 SNXFXY+URWPalladioL-Bold Type 1 Custom yes yes no 95 0 WNWTFR+VnURWPalladioL-Bold Type 1 Custom yes yes no 96 0 TAGICD+URWPalladioL-Roma Type 1 Custom yes yes no 97 0 NJJCXD+VnURWPalladioL Type 1 Custom yes yes no 98 0 OFLXAT+Rpxr Type 1 Builtin yes yes no 99 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 104 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 105 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 124 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 125 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 126 0 HHMDGK+Pxsy Type 1 Builtin yes yes no 174 0 KKLODL+PalatinoLinotype TrueType WinAnsi yes yes no 191 0 KKLOHL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 192 0 KKLOKM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 193 0 KKLPMH+TimesNewRoman CID TrueType Identity-H yes yes yes 194 0 KKLODK+PalatinoLinotype CID TrueType Identity-H yes yes yes 214 0 KKLODL+PalatinoLinotype TrueType WinAnsi yes yes no 215 0 KKLOHL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 216 0 KKLOKM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 217 0 KKLPMH+TimesNewRoman CID TrueType Identity-H yes yes yes 218 0 GBLQZB+Rpxi Type 1 Builtin yes yes no 244 0 KKLODK+PalatinoLinotype CID TrueType Identity-H yes yes yes 250 0 KKLODL+PalatinoLinotype TrueType WinAnsi yes yes no 251 0 KKLOHL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 252 0 KKLOKM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 253 0 KKLPMH+TimesNewRoman CID TrueType Identity-H yes yes yes 254 0 KKLODL+PalatinoLinotype TrueType WinAnsi yes yes no 288 0 KKLOHL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 289 0 KKLOKM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 290 0 KKLPMH+TimesNewRoman CID TrueType Identity-H yes yes yes 291 0 KKLODL+PalatinoLinotype TrueType WinAnsi yes yes no 337 0 KKLOHL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 338 0 KKLOKM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 339 0 KKLPMH+TimesNewRoman CID TrueType Identity-H yes yes yes 340 0 CAMXTK+EURM10 Type 1 Builtin yes yes no 371 0 UZLZOY+Rpxmi Type 1 Builtin yes yes no 442 0 VSHNAE+Rpcxr Type 1 Builtin yes yes no 523 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-09-16 02:39:12 CEST RepresentationInformation: pmc_33066346.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2020-11-09 03:37:25 CET Size: 3338874 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴどづのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰こちねばぬづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぇぬはぢちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ふぅざぜ〴ぜ〰ぐひはぴづはねづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰いどててづひづのぴどちぬぬべぜ〴ぜ〰ぅへばひづびびづつぜ〴ぜ〰ぐひはぴづどのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰あどはぬはでどっちぬぜ〴ぜ〰ぐひはっづびびづびぜ〴ぜ〰ぅのひどっとねづのぴぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: ぐちぴどづのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰こちねばぬづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぇぬはぢちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ふぅざぜ〴ぜ〰ぐひはぴづはねづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰いどててづひづのぴどちぬぬべぜ〴ぜ〰ぅへばひづびびづつぜ〴ぜ〰ぐひはぴづどのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰あどはぬはでどっちぬぜ〴ぜ〰ぐひはっづびびづびぜ〴ぜ〰ぅのひどっとねづのぴぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぇぬはぢちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ふぅざぜ〴ぜ〰ぐひはぴづはねづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰いどててづひづのぴどちぬぬべぜ〴ぜ〰ぅへばひづびびづつぜ〴ぜ〰ぐひはぴづどのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰あどはぬはでどっちぬぜ〴ぜ〰ぐひはっづびびづびぜ〴ぜ〰ぅのひどっとねづのぴぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: いどててづひづのぴどちぬぬべぜ〴ぜ〰ぅへばひづびびづつぜ〴ぜ〰ぐひはぴづどのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰あどはぬはでどっちぬぜ〴ぜ〰ぐひはっづびびづびぜ〴ぜ〰ぅのひどっとねづのぴぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: あどはぬはでどっちぬぜ〴ぜ〰ぐひはっづびびづびぜ〴ぜ〰ぅのひどっとねづのぴぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: きちぴづひどちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴどづのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰ぐひづ〭ぐひはっづびびどのでぜ〴ぜ〰はてぜ〴ぜ〰こちねばぬづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰こちねばぬづびぜ〴ぜ〰ぐひはっづびびどのでぜ〴ぜ〰ちのつぜ〴ぜ〰ふぅざぜ〴ぜ〰ぉびはぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰きちびび〭こばづっぴひはねづぴひべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぐひはぴづはねどっびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Children: Item: Title: ぐちぴどづのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰ぐひづ〭ぐひはっづびびどのでぜ〴ぜ〰はてぜ〴ぜ〰こちねばぬづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰こちねばぬづびぜ〴ぜ〰ぐひはっづびびどのでぜ〴ぜ〰ちのつぜ〴ぜ〰ふぅざぜ〴ぜ〰ぉびはぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰きちびび〭こばづっぴひはねづぴひべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぐひはぴづはねどっびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: こちねばぬづびぜ〴ぜ〰ぐひはっづびびどのでぜ〴ぜ〰ちのつぜ〴ぜ〰ふぅざぜ〴ぜ〰ぉびはぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰きちびび〭こばづっぴひはねづぴひべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぐひはぴづはねどっびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: きちびび〭こばづっぴひはねづぴひべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぐひはぴづはねどっびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぐひはぴづはねどっびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぐちぴづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: WNWTFR+VnURWPalladioL-Bold FontSubset: true FirstChar: 160 LastChar: 160 FontDescriptor: FontName: WNWTFR+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: TAGICD+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: TAGICD+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NJJCXD+VnURWPalladioL FontSubset: true FirstChar: 145 LastChar: 226 FontDescriptor: FontName: NJJCXD+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: OFLXAT+Rpxr FontSubset: true FirstChar: 11 LastChar: 62 FontDescriptor: FontName: OFLXAT+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: CAMXTK+EURM10 FontSubset: true FirstChar: 12 LastChar: 22 FontDescriptor: FontName: CAMXTK+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: GBLQZB+Rpxi FontSubset: true FirstChar: 11 LastChar: 11 FontDescriptor: FontName: GBLQZB+Rpxi Flags: Symbolic FontBBox: -162, -280, 856, 733 FontFile: true Font: BaseFont: UZLZOY+Rpxmi FontSubset: true FirstChar: 58 LastChar: 58 FontDescriptor: FontName: UZLZOY+Rpxmi Flags: Symbolic FontBBox: -70, -289, 949, 802 FontFile: true Font: BaseFont: VSHNAE+Rpcxr FontSubset: true FirstChar: 169 LastChar: 169 FontDescriptor: FontName: VSHNAE+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: UFOIXQ+URWPalladioL-Ital FontSubset: true FirstChar: 45 LastChar: 121 FontDescriptor: FontName: UFOIXQ+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HHMDGK+Pxsy FontSubset: true FirstChar: 0 LastChar: 14 FontDescriptor: FontName: HHMDGK+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Font: BaseFont: SNXFXY+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 241 FontDescriptor: FontName: SNXFXY+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 221, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 178, 628, 189, 641 Annotation: Subtype: Link Rect: 447, 628, 458, 641 Annotation: Subtype: Link Rect: 466, 452, 518, 471 Annotation: Subtype: Link Rect: 317, 171, 324, 180 ActionDest: 438 Annotation: Subtype: Link Rect: 325, 171, 332, 180 ActionDest: 438 Annotation: Subtype: Link Rect: 349, 157, 356, 166 ActionDest: 438 Annotation: Subtype: Link Rect: 358, 157, 365, 166 ActionDest: 438 Annotation: Subtype: Link Rect: 308, 103, 315, 112 ActionDest: 438 Annotation: Subtype: Link Rect: 303, 90, 310, 99 ActionDest: 438 Annotation: Subtype: Link Rect: 393, 76, 399, 85 ActionDest: 438 Annotation: Subtype: Link Rect: 193, 38, 270, 50 Annotation: Subtype: Link Rect: 416, 38, 519, 50 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 445, 742, 452, 752 ActionDest: 438 Annotation: Subtype: Link Rect: 131, 715, 143, 725 ActionDest: 438 Annotation: Subtype: Link Rect: 146, 715, 158, 725 ActionDest: 469 Annotation: Subtype: Link Rect: 390, 702, 402, 711 ActionDest: 469 Annotation: Subtype: Link Rect: 402, 702, 414, 711 ActionDest: 469 Annotation: Subtype: Link Rect: 426, 688, 438, 698 ActionDest: 469 Annotation: Subtype: Link Rect: 439, 688, 451, 698 ActionDest: 469 Annotation: Subtype: Link Rect: 491, 661, 503, 671 ActionDest: 469 Annotation: Subtype: Link Rect: 503, 661, 515, 671 ActionDest: 469 Annotation: Subtype: Link Rect: 203, 634, 214, 644 ActionDest: 469 Annotation: Subtype: Link Rect: 305, 607, 317, 617 ActionDest: 469 Annotation: Subtype: Link Rect: 402, 458, 409, 470 ActionDest: 171 Annotation: Subtype: Link Rect: 303, 404, 310, 416 ActionDest: 171 Annotation: Subtype: Link Rect: 172, 258, 184, 267 ActionDest: 469 Annotation: Subtype: Link Rect: 503, 258, 515, 267 ActionDest: 469 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 486, 68, 493, 80 ActionDest: 183 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 475, 434, 482, 446 ActionDest: 183 Annotation: Subtype: Link Rect: 491, 380, 498, 392 ActionDest: 183 Annotation: Subtype: Link Rect: 501, 366, 508, 378 ActionDest: 183 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 501, 707, 508, 719 ActionDest: 241 Annotation: Subtype: Link Rect: 384, 263, 391, 275 ActionDest: 241 Annotation: Subtype: Link Rect: 438, 236, 444, 248 ActionDest: 241 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 368, 686, 375, 698 ActionDest: 280 Annotation: Subtype: Link Rect: 504, 198, 511, 209 ActionDest: 280 Annotation: Subtype: Link Rect: 279, 130, 286, 142 ActionDest: 329 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 415, 342, 427, 351 ActionDest: 469 Annotation: Subtype: Link Rect: 430, 342, 442, 351 ActionDest: 469 Annotation: Subtype: Link Rect: 217, 220, 229, 229 ActionDest: 469 Annotation: Subtype: Link Rect: 441, 125, 453, 135 ActionDest: 438 Annotation: Subtype: Link Rect: 455, 126, 467, 135 ActionDest: 469 Annotation: Subtype: Link Rect: 99, 99, 111, 108 ActionDest: 469 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 391, 729, 403, 738 ActionDest: 469 Annotation: Subtype: Link Rect: 160, 702, 172, 711 ActionDest: 469 Annotation: Subtype: Link Rect: 172, 702, 184, 711 ActionDest: 508 Annotation: Subtype: Link Rect: 366, 688, 378, 698 ActionDest: 508 Annotation: Subtype: Link Rect: 379, 688, 391, 698 ActionDest: 508 Annotation: Subtype: Link Rect: 376, 675, 388, 684 ActionDest: 508 Annotation: Subtype: Link Rect: 389, 675, 401, 684 ActionDest: 508 Annotation: Subtype: Link Rect: 405, 580, 417, 590 ActionDest: 508 Annotation: Subtype: Link Rect: 432, 567, 444, 576 ActionDest: 508 Annotation: Subtype: Link Rect: 185, 540, 197, 549 ActionDest: 508 Annotation: Subtype: Link Rect: 112, 513, 124, 522 ActionDest: 508 Annotation: Subtype: Link Rect: 124, 513, 136, 522 ActionDest: 508 Annotation: Subtype: Link Rect: 503, 499, 515, 508 ActionDest: 508 Annotation: Subtype: Link Rect: 434, 391, 446, 400 ActionDest: 469 Annotation: Subtype: Link Rect: 134, 351, 146, 360 ActionDest: 508 Annotation: Subtype: Link Rect: 278, 297, 290, 306 ActionDest: 508 Annotation: Subtype: Link Rect: 291, 297, 303, 306 ActionDest: 508 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 117, 551, 129, 560 ActionDest: 508 Annotation: Subtype: Link Rect: 398, 441, 410, 450 ActionDest: 508 Annotation: Subtype: Link Rect: 128, 166, 243, 178 Annotation: Subtype: Link Rect: 251, 168, 263, 178 ActionDest: 508 Annotation: Subtype: Link Rect: 257, 155, 269, 164 ActionDest: 508 Annotation: Subtype: Link Rect: 196, 83, 298, 94 Annotation: Subtype: Link Rect: 401, 85, 413, 94 ActionDest: 508 Annotation: Subtype: Link Rect: 413, 85, 425, 94 ActionDest: 508 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 206, 740, 336, 752 Annotation: Subtype: Link Rect: 343, 742, 355, 752 ActionDest: 508 Annotation: Subtype: Link Rect: 465, 742, 476, 752 ActionDest: 520 Annotation: Subtype: Link Rect: 75, 726, 231, 738 Annotation: Subtype: Link Rect: 451, 648, 462, 657 ActionDest: 520 Annotation: Subtype: Link Rect: 354, 621, 366, 630 ActionDest: 520 Annotation: Subtype: Link Rect: 359, 500, 519, 511 Annotation: Subtype: Link Rect: 75, 490, 106, 500 Annotation: Subtype: Link Rect: 366, 417, 443, 428 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 100, 323, 137, 333 Annotation: Subtype: Link Rect: 143, 323, 179, 333 Annotation: Subtype: Link Rect: 480, 309, 516, 320 Annotation: Subtype: Link Rect: 433, 271, 471, 282 Annotation: Subtype: Link Rect: 477, 271, 513, 282 Annotation: Subtype: Link Rect: 480, 245, 516, 256 Annotation: Subtype: Link Rect: 99, 233, 134, 243 Annotation: Subtype: Link Rect: 261, 206, 297, 217 Annotation: Subtype: Link Rect: 176, 181, 213, 191 Annotation: Subtype: Link Rect: 438, 154, 476, 165 Annotation: Subtype: Link Rect: 186, 129, 223, 140 Annotation: Subtype: Link Rect: 274, 103, 311, 114 Annotation: Subtype: Link Rect: 227, 77, 264, 88 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 224, 727, 262, 738 Annotation: Subtype: Link Rect: 268, 727, 304, 738 Annotation: Subtype: Link Rect: 244, 701, 282, 712 Annotation: Subtype: Link Rect: 288, 701, 324, 712 Annotation: Subtype: Link Rect: 100, 663, 137, 673 Annotation: Subtype: Link Rect: 478, 637, 516, 648 Annotation: Subtype: Link Rect: 100, 625, 136, 635 Annotation: Subtype: Link Rect: 100, 586, 137, 596 Annotation: Subtype: Link Rect: 143, 586, 179, 596 Annotation: Subtype: Link Rect: 436, 559, 474, 570 Annotation: Subtype: Link Rect: 386, 533, 424, 544 Annotation: Subtype: Link Rect: 316, 508, 353, 519 Annotation: Subtype: Link Rect: 474, 469, 511, 480 Annotation: Subtype: Link Rect: 235, 431, 272, 441 Annotation: Subtype: Link Rect: 172, 392, 210, 402 Annotation: Subtype: Link Rect: 216, 392, 252, 402 Annotation: Subtype: Link Rect: 100, 341, 137, 351 Annotation: Subtype: Link Rect: 143, 341, 179, 351 Annotation: Subtype: Link Rect: 180, 302, 218, 312 Annotation: Subtype: Link Rect: 224, 302, 260, 312 Annotation: Subtype: Link Rect: 266, 249, 304, 260 Annotation: Subtype: Link Rect: 331, 211, 368, 222 Annotation: Subtype: Link Rect: 252, 172, 289, 183 Annotation: Subtype: Link Rect: 479, 133, 516, 144 Annotation: Subtype: Link Rect: 99, 95, 136, 105 Annotation: Subtype: Link Rect: 169, 69, 205, 80 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 100, 728, 137, 738 Annotation: Subtype: Link Rect: 238, 701, 275, 712 Annotation: Subtype: Link Rect: 100, 676, 137, 686 Annotation: Subtype: Link Rect: 143, 676, 179, 686 Annotation: Subtype: Link Rect: 181, 638, 219, 648 Annotation: Subtype: Link Rect: 225, 638, 261, 648 Annotation: Subtype: Link Rect: 100, 599, 137, 609 Annotation: Subtype: Link Rect: 143, 599, 179, 609 Annotation: Subtype: Link Rect: 216, 572, 254, 583 Annotation: Subtype: Link Rect: 260, 572, 296, 583 Annotation: Subtype: Link Rect: 426, 546, 463, 559 Annotation: Subtype: Link Rect: 469, 546, 505, 559 Annotation: Subtype: Link Rect: 145, 521, 183, 531 Annotation: Subtype: Link Rect: 189, 521, 225, 531 Annotation: Subtype: Link Rect: 440, 495, 477, 506 Annotation: Subtype: Link Rect: 229, 457, 266, 467 Annotation: Subtype: Link Rect: 366, 417, 404, 428 Annotation: Subtype: Link Rect: 237, 391, 274, 402 Annotation: Subtype: Link Rect: 280, 391, 316, 402 Annotation: Subtype: Link Rect: 136, 354, 174, 364 Annotation: Subtype: Link Rect: 180, 354, 216, 364 Annotation: Subtype: Link Rect: 215, 315, 253, 325 Annotation: Subtype: Link Rect: 259, 315, 295, 325 Annotation: Subtype: Link Rect: 349, 288, 386, 299 Annotation: Subtype: Link Rect: 261, 250, 299, 260 Annotation: Subtype: Link Rect: 305, 250, 341, 260 Annotation: Subtype: Link Rect: 150, 224, 188, 234 Annotation: Subtype: Link Rect: 459, 198, 496, 209 Annotation: Subtype: Link Rect: 359, 159, 396, 170 Annotation: Subtype: Link Rect: 442, 120, 480, 131 Annotation: Subtype: Link Rect: 379, 94, 416, 105 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 100, 715, 137, 725 Annotation: Subtype: Link Rect: 143, 715, 179, 725 Annotation: Subtype: Link Rect: 100, 663, 137, 673 Annotation: Subtype: Link Rect: 143, 663, 179, 673 Annotation: Subtype: Link Rect: 321, 637, 357, 648 Annotation: Subtype: Link Rect: 363, 637, 398, 648 Annotation: Subtype: Link Rect: 76, 565, 166, 596 Annotation: Subtype: Link Rect: 234, 559, 407, 570 Checksum: 33a6099b Type: CRC32 Checksum: ab0e4ad7900183b5350ba591eac1b6f5 Type: MD5 Checksum: 5d424f681b3301676dceb99687c64e4128f26b48 Type: SHA-1