ad5592718d07792cd4f339aa378f7956 pmc_31344857.pdf fd1ee55c94a68209817640f64937f4eb866ebc31 pmc_31344857.pdf 8d79aec1acad020e19b318ef811cece258b0bf4e5417bb9260fade72aa150310 pmc_31344857.pdf Title: SOCS1-Derived Peptide Administered by Eye Drops Prevents Retinal Neuroinflammation and Vascular Leakage in Experimental Diabetes Subject: Current treatments for diabetic retinopathy (DR) target late stages when vision has already been significantly affected. Accumulating evidence suggests that neuroinflammation plays a major role in the pathogenesis of DR, resulting in the disruption of the blood-retinal barrier. Suppressors of cytokine signaling (SOCS) are cytokine-inducible proteins that function as a negative feedback loop regulating cytokine responses. On this basis, the aim of the present study was to evaluate the effect of a SOCS1-derived peptide administered by eye drops (2 weeks) on retinal neuroinflammation and early microvascular abnormalities in a db/db mouse model. In brief, we found that SOCS1-derived peptide significantly reduced glial activation and neural apoptosis induced by diabetes, as well as retinal levels of proinflammatory cytokines. Moreover, a significant improvement of electroretinogram parameters was observed, thus revealing a clear impact of the histological findings on global retinal function. Finally, SOCS1-derived peptide prevented the disruption of the blood-retinal barrier. Overall, our results suggest that topical administration of SOCS1-derived peptide is effective in preventing retinal neuroinflammation and early microvascular impairment. These findings could open up a new strategy for the treatment of early stages of DR. Keywords: diabetic retinopathy; neuroinflammation; suppressors of cytokine signaling; microvascular impairment; db/db mouse Author: Cristina Hernández, Patricia Bogdanov, Carmen Gómez-Guerrero, Joel Sampedro, Cristina Solà-Adell, Carmen Espejo, Marta García-Ramírez, Ignacio Prieto, Jesús Egido and Rafael Simó Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.19 CreationDate: Wed Jul 24 11:25:07 2019 CEST ModDate: Wed Jul 24 11:25:07 2019 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 20 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 6835644 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- INWMMJ+URWPalladioL-Ital Type 1 Custom yes yes no 134 0 QLXGFU+URWPalladioL-Bold Type 1 Custom yes yes no 135 0 CCDETI+VnURWPalladioL-Bold Type 1 Custom yes yes no 136 0 QTLELQ+Pxbsy Type 1 Builtin yes yes no 137 0 YPGYDS+URWPalladioL-Roma Type 1 Custom yes yes no 138 0 CMFVHJ+VnURWPalladioL Type 1 Custom yes yes no 139 0 FATHTC+Rpxr Type 1 Builtin yes yes no 140 0 XHPFNY+Pxsy Type 1 Builtin yes yes no 141 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 146 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 147 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 166 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 167 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 168 0 HQJNFB+EURM10 Type 1 Builtin yes yes no 201 0 GBLQZB+Rpxi Type 1 Builtin yes yes no 226 0 DAMLID+PalatinoLinotype CID TrueType Identity-H yes yes yes 233 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 234 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 235 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 236 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 237 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 271 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 272 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 273 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 274 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 303 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 304 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 305 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 306 0 DANEFF+Symbol Type 1C Custom yes yes yes 334 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 335 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 336 0 DAMLPF+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 337 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 338 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 339 0 DANECF+TimesNewRoman,Bold CID TrueType Identity-H yes yes yes 340 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 381 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 382 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 383 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 384 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 413 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 414 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 415 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 416 0 DAMLID+PalatinoLinotype CID TrueType Identity-H yes yes yes 445 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 446 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 447 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 448 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 449 0 DAMLID+PalatinoLinotype CID TrueType Identity-H yes yes yes 487 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 488 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 489 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 490 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 491 0 DAMLID+PalatinoLinotype CID TrueType Identity-H yes yes yes 524 0 DAOCDC+CambriaMath CID TrueType Identity-H yes yes yes 525 0 DAMLJE+PalatinoLinotype TrueType WinAnsi yes yes no 526 0 DAMLNE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 527 0 DAMLPG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 528 0 DAMMLC+TimesNewRoman CID TrueType Identity-H yes yes yes 529 0 DAOCCC+Calibri CID TrueType Identity-H yes yes yes 530 0 KSGHMQ+PazoMath Type 1 Builtin yes yes no 639 0 THGEKM+Rpxsc Type 1 Builtin yes yes no 666 0 TGMEOR+Rpcxr Type 1 Builtin yes yes no 757 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2020-11-19 06:11:43 CET RepresentationInformation: pmc_31344857.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2020-08-03 03:41:01 CEST Size: 6835644 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〰ぎづふひはばひはぴづっぴどぶづぜ〴ぜ〰ぅててづっぴびぜ〴ぜ〰はてぜ〴ぜ〰ごはばどっちぬぜ〴ぜ〰ぁつねどのどびぴひちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰こくぃこ〱ぜ〴ぜ〰ぐづばぴどつはねどねづぴどっぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸱⸱ Children: Item: Title: ぎづふひはばひはぴづっぴどぶづぜ〴ぜ〰ぅててづっぴびぜ〴ぜ〰はてぜ〴ぜ〰ごはばどっちぬぜ〴ぜ〰ぁつねどのどびぴひちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰こくぃこ〱ぜ〴ぜ〰ぐづばぴどつはねどねづぴどっぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸱⸱ Children: Item: Title: きぜ㌷㑜〰ぬぬづひぜ〴ぜ〰ぇぬどちぬぜ〴ぜ〰ぃづぬぬびぜ〴ぜ〰ぁっぴどぶちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸱⸲ Item: Title: きどっひはでぬどちぬぜ〴ぜ〰ぁっぴどぶちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸱⸳ Item: Title: ぁばはばぴはびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸱⸴ Item: Title: ぅげぇぜ〴ぜ〰ぁぢのはひねちぬどぴどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰こくぃこ〱ぜ〴ぜ〰ごひづちぴねづのぴぜ〴ぜ〰ぐひづぶづのぴびぜ〴ぜ〰ざちびっふぬちひぜ〴ぜ〰がづちにちでづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰きづっとちのどびねびぜ〴ぜ〰はてぜ〴ぜ〰ぁっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸱ Item: Title: こくぃこ〱ぜ〴ぜ〰ごひづちぴねづのぴぜ〴ぜ〰ぐひづぶづのぴびぜ〴ぜ〰ざちびっふぬちひぜ〴ぜ〰がづちにちでづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰きづっとちのどびねびぜ〴ぜ〰はてぜ〴ぜ〰ぁっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸱ Item: Title: きづっとちのどびねびぜ〴ぜ〰はてぜ〴ぜ〰ぁっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸱ Children: Item: Title: ぇぬふぴちねちぴづぜ〴ぜ〰きづぴちぢはぬどびねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸲ Item: Title: ぅへばひづびびどはのぜ〴ぜ〰はてぜ〴ぜ〰ぐひはどのてぬちねねちぴはひべぜ〴ぜ〰ぃべぴはにどのづびぜ〴ぜ〰ちのつぜ〴ぜ〰ざぅぇうぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸲⸳⸳ Item: Title: こくぃこ〱ぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰こふばばひづびびづびぜ〴ぜ〰こごぁごぜ〴ぜ〰ぁっぴどぶちぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰いはぷのびぴひづちねぜ〴ぜ〰ぇづのづぜ〴ぜ〰ぅへばひづびびどはのぜ〴ぜ〰どのぜ〴ぜ〰えふねちのぜ〴ぜ〰げづぴどのちぬぜ〴ぜ〰ぐどでねづのぴぜ〴ぜ〰ぅばどぴとづぬどちぬぜ〴ぜ〰ぃづぬぬびぜ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〰ぁのどねちぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰こくぃこ〱ぜ〴ぜ〰いづひどぶづつぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰きぉこ〱ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぅぬづっぴひはひづぴどのはでひちねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉねねふのはてぬふはひづびっづのっづぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Children: Item: Title: ぁのどねちぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㈩‾㸊⡜㌷㙜㌷㝜〰こくぃこ〱ぜ〴ぜ〰いづひどぶづつぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰きぉこ〱ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぅぬづっぴひはひづぴどのはでひちねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉねねふのはてぬふはひづびっづのっづぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Item: Title: こくぃこ〱ぜ〴ぜ〰いづひどぶづつぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぜ〵ぜ〰きぉこ〱ぜ〵ㅜ〰ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㌩‾㸊⡜㌷㙜㌷㝜〰ぅぬづっぴひはひづぴどのはでひちねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉねねふのはてぬふはひづびっづのっづぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Item: Title: ぅぬづっぴひはひづぴどのはでひちねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㐩‾㸊⡜㌷㙜㌷㝜〰ぉねねふのはてぬふはひづびっづのっづぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Item: Title: ぉねねふのはてぬふはひづびっづのっづぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸱ Children: Item: Title: ぁのちぬべびどびぜ〴ぜ〰てはひぜ〴ぜ〰ぇぬどちぬぜ〴ぜ〰ぁっぴどぶちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸴⸴⸲ Item: Title: ぁばはばぴはびどびぜ〴ぜ〰ぁびびづびびねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㔩‾㸊⡜㌷㙜㌷㝜〰きづちびふひづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰げづぴどのちぬぜ〴ぜ〰ざちびっふぬちひぜ〴ぜ〰ぐづひねづちぢどぬどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰ぇぬふぴちねちぴづぜ〴ぜ〰けふちのぴどてどっちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㜩‾㸊⡜㌷㙜㌷㝜〰きづちびふひづねづのぴびぜ〴ぜ〰はてぜ〴ぜ〰ぃべぴはにどのづぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㠩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぴひはぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰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⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰げづてづひづのっづび Item: Title: きづちびふひづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰げづぴどのちぬぜ〴ぜ〰ざちびっふぬちひぜ〴ぜ〰ぐづひねづちぢどぬどぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㘩‾㸊⡜㌷㙜㌷㝜〰ぇぬふぴちねちぴづぜ〴ぜ〰けふちのぴどてどっちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㜩‾㸊⡜㌷㙜㌷㝜〰きづちびふひづねづのぴびぜ〴ぜ〰はてぜ〴ぜ〰ぃべぴはにどのづぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㠩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぴひはぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰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⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰げづてづひづのっづび Item: Title: ぇぬふぴちねちぴづぜ〴ぜ〰けふちのぴどてどっちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㜩‾㸊⡜㌷㙜㌷㝜〰きづちびふひづねづのぴびぜ〴ぜ〰はてぜ〴ぜ〰ぃべぴはにどのづぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㠩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぴひはぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰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⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰げづてづひづのっづび Item: Title: きづちびふひづねづのぴびぜ〴ぜ〰はてぜ〴ぜ〰ぃべぴはにどのづぜ〴ぜ〰ぅへばひづびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㠩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰ざどぴひはぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰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⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰げづてづひづのっづび Item: Title: ぉのぜ〴ぜ〰ざどぴひはぜ〴ぜ〰こぴふつどづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰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⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰げづてづひづのっづび Item: Title: 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⡳畢獥捴楯渮㐮㤩‾㸊⡜㌷㙜㌷㝜〰げづてづひづのっづび Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode FilterPipeline: DCTDecode Images: Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 34 ImageHeight: 39 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 34 ImageHeight: 39 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Fonts: Type1: 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: INWMMJ+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: INWMMJ+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QLXGFU+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: QLXGFU+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CCDETI+VnURWPalladioL-Bold FontSubset: true FirstChar: 160 LastChar: 243 FontDescriptor: FontName: CCDETI+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QTLELQ+Pxbsy FontSubset: true FirstChar: 121 LastChar: 121 FontDescriptor: FontName: QTLELQ+Pxbsy Flags: Symbolic FontBBox: 5, -978, 1382, 913 FontFile: true Font: BaseFont: HQJNFB+EURM10 FontSubset: true FirstChar: 11 LastChar: 22 FontDescriptor: FontName: HQJNFB+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: YPGYDS+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: YPGYDS+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CMFVHJ+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 226 FontDescriptor: FontName: CMFVHJ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: FATHTC+Rpxr FontSubset: true FirstChar: 11 LastChar: 61 FontDescriptor: FontName: FATHTC+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: XHPFNY+Pxsy FontSubset: true FirstChar: 0 LastChar: 121 FontDescriptor: FontName: XHPFNY+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Font: BaseFont: TGMEOR+Rpcxr FontSubset: true FirstChar: 169 LastChar: 174 FontDescriptor: FontName: TGMEOR+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: THGEKM+Rpxsc FontSubset: true FirstChar: 100 LastChar: 108 FontDescriptor: FontName: THGEKM+Rpxsc Flags: Symbolic FontBBox: -37, -172, 852, 718 FontFile: true Font: BaseFont: KSGHMQ+PazoMath FontSubset: true FirstChar: 68 LastChar: 83 FontDescriptor: FontName: KSGHMQ+PazoMath Flags: Symbolic FontBBox: -40, -283, 878, 946 FontFile: 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: 191, 640, 202, 654 Annotation: Subtype: Link Rect: 308, 640, 319, 654 Annotation: Subtype: Link Rect: 155, 626, 166, 640 Annotation: Subtype: Link Rect: 351, 626, 362, 640 Annotation: Subtype: Link Rect: 479, 626, 490, 640 Annotation: Subtype: Link Rect: 321, 613, 332, 626 Annotation: Subtype: Link Rect: 466, 462, 518, 481 Annotation: Subtype: Link Rect: 212, 99, 219, 108 ActionDest: 693 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, 743, 452, 752 ActionDest: 693 Annotation: Subtype: Link Rect: 148, 715, 155, 725 ActionDest: 693 Annotation: Subtype: Link Rect: 180, 621, 187, 630 ActionDest: 693 Annotation: Subtype: Link Rect: 190, 621, 197, 630 ActionDest: 693 Annotation: Subtype: Link Rect: 488, 580, 500, 590 ActionDest: 693 Annotation: Subtype: Link Rect: 503, 580, 515, 590 ActionDest: 693 Annotation: Subtype: Link Rect: 281, 553, 293, 562 ActionDest: 693 Annotation: Subtype: Link Rect: 224, 540, 231, 549 ActionDest: 693 Annotation: Subtype: Link Rect: 326, 526, 338, 535 ActionDest: 693 Annotation: Subtype: Link Rect: 227, 486, 239, 495 ActionDest: 693 Annotation: Subtype: Link Rect: 240, 486, 252, 495 ActionDest: 693 Annotation: Subtype: Link Rect: 368, 432, 380, 441 ActionDest: 693 Annotation: Subtype: Link Rect: 469, 364, 481, 373 ActionDest: 693 Annotation: Subtype: Link Rect: 320, 351, 332, 360 ActionDest: 693 Annotation: Subtype: Link Rect: 332, 351, 344, 360 ActionDest: 693 Annotation: Subtype: Link Rect: 269, 324, 280, 333 ActionDest: 730 Annotation: Subtype: Link Rect: 503, 310, 515, 319 ActionDest: 730 Annotation: Subtype: Link Rect: 474, 270, 486, 279 ActionDest: 730 Annotation: Subtype: Link Rect: 503, 256, 515, 265 ActionDest: 730 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 451, 670, 458, 682 ActionDest: 223 Annotation: Subtype: Link Rect: 303, 256, 310, 267 ActionDest: 223 Annotation: Subtype: Link Rect: 337, 172, 344, 184 ActionDest: 263 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 458, 141, 465, 153 ActionDest: 296 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 109, 176, 116, 188 ActionDest: 327 Annotation: Subtype: Link Rect: 385, 149, 392, 161 ActionDest: 327 Page: Sequence: 6 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 160, 693, 167, 705 ActionDest: 372 Annotation: Subtype: Link Rect: 414, 680, 421, 692 ActionDest: 372 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 141, 684, 147, 695 ActionDest: 405 Annotation: Subtype: Link Rect: 271, 154, 283, 163 ActionDest: 730 Annotation: Subtype: Link Rect: 250, 124, 257, 136 ActionDest: 405 Annotation: Subtype: Link Rect: 227, 68, 234, 80 ActionDest: 437 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 489, 195, 495, 207 ActionDest: 480 Annotation: Subtype: Link Rect: 229, 168, 236, 180 ActionDest: 480 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 135, 144, 142, 156 ActionDest: 515 Annotation: Subtype: Link Rect: 236, 144, 243, 156 ActionDest: 515 Annotation: Subtype: Link Rect: 108, 104, 115, 116 ActionDest: 515 Annotation: Subtype: Link Rect: 285, 90, 292, 102 ActionDest: 515 Page: Sequence: 11 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 174, 615, 186, 624 ActionDest: 693 Annotation: Subtype: Link Rect: 186, 615, 198, 624 ActionDest: 693 Annotation: Subtype: Link Rect: 113, 574, 125, 584 ActionDest: 730 Annotation: Subtype: Link Rect: 304, 561, 316, 570 ActionDest: 730 Annotation: Subtype: Link Rect: 369, 534, 381, 543 ActionDest: 730 Annotation: Subtype: Link Rect: 384, 534, 396, 543 ActionDest: 730 Annotation: Subtype: Link Rect: 305, 466, 317, 475 ActionDest: 730 Annotation: Subtype: Link Rect: 317, 466, 329, 475 ActionDest: 730 Annotation: Subtype: Link Rect: 142, 426, 154, 435 ActionDest: 730 Annotation: Subtype: Link Rect: 402, 358, 414, 367 ActionDest: 730 Annotation: Subtype: Link Rect: 111, 318, 123, 327 ActionDest: 730 Annotation: Subtype: Link Rect: 111, 291, 123, 300 ActionDest: 730 Annotation: Subtype: Link Rect: 192, 264, 204, 273 ActionDest: 730 Annotation: Subtype: Link Rect: 443, 250, 450, 259 ActionDest: 693 Annotation: Subtype: Link Rect: 451, 250, 463, 259 ActionDest: 693 Annotation: Subtype: Link Rect: 466, 250, 478, 259 ActionDest: 693 Annotation: Subtype: Link Rect: 434, 196, 446, 205 ActionDest: 730 Annotation: Subtype: Link Rect: 447, 196, 459, 205 ActionDest: 730 Annotation: Subtype: Link Rect: 139, 169, 151, 178 ActionDest: 730 Annotation: Subtype: Link Rect: 380, 115, 392, 124 ActionDest: 730 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 504, 742, 516, 752 ActionDest: 730 Annotation: Subtype: Link Rect: 468, 729, 480, 738 ActionDest: 730 Annotation: Subtype: Link Rect: 103, 688, 115, 698 ActionDest: 730 Annotation: Subtype: Link Rect: 111, 648, 123, 657 ActionDest: 753 Annotation: Subtype: Link Rect: 124, 621, 136, 630 ActionDest: 753 Annotation: Subtype: Link Rect: 296, 526, 303, 535 ActionDest: 693 Annotation: Subtype: Link Rect: 325, 499, 332, 508 ActionDest: 693 Annotation: Subtype: Link Rect: 481, 432, 488, 441 ActionDest: 693 Annotation: Subtype: Link Rect: 488, 432, 495, 441 ActionDest: 693 Annotation: Subtype: Link Rect: 496, 432, 503, 441 ActionDest: 693 Annotation: Subtype: Link Rect: 503, 432, 515, 441 ActionDest: 753 Annotation: Subtype: Link Rect: 503, 391, 515, 400 ActionDest: 753 Annotation: Subtype: Link Rect: 455, 310, 467, 319 ActionDest: 753 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 277, 729, 289, 738 ActionDest: 730 Annotation: Subtype: Link Rect: 342, 715, 349, 725 ActionDest: 693 Annotation: Subtype: Link Rect: 350, 715, 357, 725 ActionDest: 693 Annotation: Subtype: Link Rect: 357, 715, 369, 725 ActionDest: 753 Annotation: Subtype: Link Rect: 487, 553, 499, 562 ActionDest: 730 Annotation: Subtype: Link Rect: 392, 361, 448, 373 Annotation: Subtype: Link Rect: 321, 157, 333, 166 ActionDest: 753 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 158, 605, 165, 617 ActionDest: 645 Annotation: Subtype: Link Rect: 244, 188, 256, 197 ActionDest: 753 Annotation: Subtype: Link Rect: 416, 188, 428, 197 ActionDest: 730 Annotation: Subtype: Link Rect: 461, 185, 468, 197 ActionDest: 655 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 142, 421, 154, 431 ActionDest: 753 Annotation: Subtype: Link Rect: 157, 422, 168, 431 ActionDest: 753 Annotation: Subtype: Link Rect: 251, 311, 263, 320 ActionDest: 753 Page: Sequence: 17 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 231, 620, 269, 631 Annotation: Subtype: Link Rect: 275, 620, 311, 631 Annotation: Subtype: Link Rect: 295, 556, 332, 566 Annotation: Subtype: Link Rect: 338, 556, 375, 566 Annotation: Subtype: Link Rect: 304, 517, 342, 528 Annotation: Subtype: Link Rect: 395, 478, 432, 489 Annotation: Subtype: Link Rect: 439, 478, 475, 489 Annotation: Subtype: Link Rect: 391, 439, 428, 450 Annotation: Subtype: Link Rect: 145, 401, 183, 412 Annotation: Subtype: Link Rect: 332, 362, 369, 373 Annotation: Subtype: Link Rect: 405, 323, 442, 334 Annotation: Subtype: Link Rect: 100, 298, 137, 308 Annotation: Subtype: Link Rect: 294, 272, 332, 282 Annotation: Subtype: Link Rect: 338, 272, 374, 282 Annotation: Subtype: Link Rect: 479, 259, 516, 270 Annotation: Subtype: Link Rect: 100, 247, 136, 257 Annotation: Subtype: Link Rect: 324, 220, 361, 231 Annotation: Subtype: Link Rect: 368, 220, 404, 231 Annotation: Subtype: Link Rect: 145, 182, 182, 192 Annotation: Subtype: Link Rect: 189, 182, 225, 192 Annotation: Subtype: Link Rect: 449, 155, 487, 166 Annotation: Subtype: Link Rect: 457, 130, 493, 140 Annotation: Subtype: Link Rect: 206, 105, 244, 115 Annotation: Subtype: Link Rect: 332, 78, 369, 89 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 336, 714, 373, 725 Annotation: Subtype: Link Rect: 251, 675, 289, 686 Annotation: Subtype: Link Rect: 207, 637, 244, 648 Annotation: Subtype: Link Rect: 250, 637, 287, 648 Annotation: Subtype: Link Rect: 136, 612, 174, 622 Annotation: Subtype: Link Rect: 180, 612, 216, 622 Annotation: Subtype: Link Rect: 100, 573, 137, 583 Annotation: Subtype: Link Rect: 143, 573, 179, 583 Annotation: Subtype: Link Rect: 223, 534, 261, 544 Annotation: Subtype: Link Rect: 267, 534, 303, 544 Annotation: Subtype: Link Rect: 136, 496, 174, 506 Annotation: Subtype: Link Rect: 180, 496, 216, 506 Annotation: Subtype: Link Rect: 184, 457, 222, 467 Annotation: Subtype: Link Rect: 228, 457, 264, 467 Annotation: Subtype: Link Rect: 480, 430, 516, 441 Annotation: Subtype: Link Rect: 302, 391, 340, 402 Annotation: Subtype: Link Rect: 159, 341, 196, 351 Annotation: Subtype: Link Rect: 311, 301, 349, 312 Annotation: Subtype: Link Rect: 478, 275, 516, 286 Annotation: Subtype: Link Rect: 100, 263, 136, 273 Annotation: Subtype: Link Rect: 394, 224, 432, 234 Annotation: Subtype: Link Rect: 438, 224, 474, 234 Annotation: Subtype: Link Rect: 416, 198, 453, 209 Annotation: Subtype: Link Rect: 460, 198, 496, 209 Annotation: Subtype: Link Rect: 343, 160, 381, 170 Annotation: Subtype: Link Rect: 387, 160, 423, 170 Annotation: Subtype: Link Rect: 229, 133, 267, 144 Annotation: Subtype: Link Rect: 273, 133, 309, 144 Annotation: Subtype: Link Rect: 368, 107, 405, 118 Annotation: Subtype: Link Rect: 411, 107, 447, 118 Annotation: Subtype: Link Rect: 145, 69, 183, 80 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 356, 715, 393, 725 Annotation: Subtype: Link Rect: 397, 675, 434, 686 Annotation: Subtype: Link Rect: 238, 637, 275, 648 Annotation: Subtype: Link Rect: 159, 599, 196, 609 Annotation: Subtype: Link Rect: 202, 599, 238, 609 Annotation: Subtype: Link Rect: 356, 572, 394, 583 Annotation: Subtype: Link Rect: 400, 572, 436, 583 Annotation: Subtype: Link Rect: 100, 534, 137, 544 Annotation: Subtype: Link Rect: 143, 534, 179, 544 Annotation: Subtype: Link Rect: 136, 496, 174, 506 Annotation: Subtype: Link Rect: 180, 496, 216, 506 Annotation: Subtype: Link Rect: 205, 431, 243, 441 Annotation: Subtype: Link Rect: 430, 404, 467, 415 Annotation: Subtype: Link Rect: 479, 378, 516, 391 Annotation: Subtype: Link Rect: 76, 336, 166, 368 Annotation: Subtype: Link Rect: 234, 331, 407, 342 Checksum: 69feeb78 Type: CRC32 Checksum: ad5592718d07792cd4f339aa378f7956 Type: MD5 Checksum: fd1ee55c94a68209817640f64937f4eb866ebc31 Type: SHA-1