4fd0726199dc7db7a47a6c07f2937e06 BRJPH_a2025v182p2487.pdf 6999be08f3cb24cf5cb381d0b78df46f5e701c92 BRJPH_a2025v182p2487.pdf c86e2ee2f0f01607a3589b2e3f6994d328f9900c2a3a62ca480b849bfb340d19 BRJPH_a2025v182p2487.pdf Title: Oral hyoscine butylbromide exerts spasmolytic effects in both gastrointestinal and urogenital tissues in rats Subject: British J Pharmacology 2025.182:2487-2502 Keywords: 10.1111/bph.17474 and colon; PK/PD study; smooth muscle; urinary bladder; uterus Author: Sara Traserra, Terence Appelqvist, Robert Lange, Maura Corsetti, Marcel Jimenez Creator: Arbortext Advanced Print Publisher 9.1.520/W Unicode Producer: Acrobat Distiller 24.0 (Windows); modified using iText 4.2.0 by 1T3XT CreationDate: Thu Apr 24 05:10:51 2025 CEST ModDate: Tue Nov 18 11:16:02 2025 CET Custom Metadata: yes Metadata Stream: yes Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 782.362 pts Page rot: 0 File size: 2078726 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ECOKMF+AdvTT6071803a.B Type 1C WinAnsi yes yes no 62 0 ECOKOF+AdvTTa9c1b374 Type 1C WinAnsi yes yes no 63 0 ECOKOG+AdvTTa9c1b374+20 Type 1C WinAnsi yes yes no 64 0 ECOKOH+AdvP4C4E74 Type 1C Custom yes yes yes 65 0 ECOKOI+AdvTTeb5f0e55.I Type 1C WinAnsi yes yes no 66 0 ECOLNE+AdvTTa9c1b374+01 Type 1C Custom yes yes yes 60 0 ECOLNF+AdvTT0459e7ca.B Type 1C WinAnsi yes yes no 61 0 ECOLND+AdvP4C4E59 Type 1C Custom yes yes yes 67 0 Times-Roman Type 1 WinAnsi no no no 5 0 ECONCP+AdvP4C4E46 Type 1C Custom yes yes no 112 0 ECONLN+AdvOT8608a8d1+20 Type 1C WinAnsi yes yes no 113 0 ECONCO+AdvOT8608a8d1+03 Type 1C Custom yes yes yes 114 0 ECPHMA+AdvTTfac587ca.B Type 1C WinAnsi yes yes no 151 0 ECPKMP+AdvTT9c438aa4.BI Type 1C WinAnsi yes yes no 159 0 ECPKMO+AdvOT8608a8d1+22 Type 1C Custom yes yes yes 160 0 EDBHEC+AdvTTa9c1b374+03 Type 1C Custom yes yes yes 228 0 EDBJND+AdvOT8608a8d1 Type 1C WinAnsi yes yes no 329 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-11-20 03:09:15 CET RepresentationInformation: BRJPH_a2025v182p2487.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-11-19 03:16:46 CET Size: 2078726 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 2 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Oral hyoscine butylbromide exerts spasmolytic effects in both gastrointestinal and urogenital tissues in rats Destination: atl_BPH_17474_ Children: Item: Title: 1 | INTRODUCTION Destination: HeadingBPH_17474bph17474-sec-0009 Item: Title: 2 | METHODS Destination: HeadingBPH_17474bph17474-sec-0010 Children: Item: Title: 2.1 | Pharmacokinetic study Destination: HeadingBPH_17474bph17474-sec-0011 Children: Item: Title: 2.1.1 | Animals and environmental conditions Destination: HeadingBPH_17474bph17474-sec-0012 Item: Title: 2.1.2 | Dosing Destination: HeadingBPH_17474bph17474-sec-0013 Item: Title: What is already known? Destination: HeadingBPH_17474bph17474-sec-0006 Item: Title: What does this study add? Destination: HeadingBPH_17474bph17474-sec-0007 Item: Title: What is the clinical significance? Destination: HeadingBPH_17474bph17474-sec-0008 Children: Item: Title: Outline placeholder Destination: unknown Children: Item: Title: 2.1.3 | Tissue collection Destination: HeadingBPH_17474bph17474-sec-0014 Item: Title: 2.1.4 | Sample extraction and analysis Destination: HeadingBPH_17474bph17474-sec-0015 Item: Title: 2.1.5 | Non‐compartmental pharmacokinetic model Destination: HeadingBPH_17474bph17474-sec-0016 Item: Title: 2.2 | Pharmacodynamic studies Destination: HeadingBPH_17474bph17474-sec-0017 Children: Item: Title: 2.2.1 | Animals and environmental conditions Destination: HeadingBPH_17474bph17474-sec-0018 Item: Title: 2.2.2 | Mechanical studies Destination: HeadingBPH_17474bph17474-sec-0019 Item: Title: 2.3 | Details of Pharmacodynamic study 1 Destination: HeadingBPH_17474bph17474-sec-0020 Children: Item: Title: 2.3.1 | Animals and mechanical activity Destination: HeadingBPH_17474bph17474-sec-0021 Item: Title: 2.3.2 | Spasmolytic activity (Study 1) Destination: HeadingBPH_17474bph17474-sec-0022 Item: Title: 2.4 | Details of Pharmacodynamic study 2 Destination: HeadingBPH_17474bph17474-sec-0023 Children: Item: Title: 2.4.1 | Animals and mechanical activity Destination: HeadingBPH_17474bph17474-sec-0024 Item: Title: 2.5 | Details of Pharmacodynamic study 3 Destination: HeadingBPH_17474bph17474-sec-0025 Children: Item: Title: 2.5.1 | Animals and drug administration Destination: HeadingBPH_17474bph17474-sec-0026 Item: Title: 2.5.2 | Mechanical activity Destination: HeadingBPH_17474bph17474-sec-0027 Item: Title: 2.6 | Measurement of spasmolytic activity (PD 2 and 3) Destination: HeadingBPH_17474bph17474-sec-0028 Item: Title: 2.7 | Data and statistical analysis Destination: HeadingBPH_17474bph17474-sec-0029 Item: Title: 2.8 | Materials Destination: HeadingBPH_17474bph17474-sec-0030 Item: Title: 2.9 | Nomenclature of targets and ligands Destination: HeadingBPH_17474bph17474-sec-0031 Item: Title: 3 | RESULTS Destination: HeadingBPH_17474bph17474-sec-0032 Children: Item: Title: 3.1 | PK study: Is HBB detectable in the CUB tissues of the rat after IV and PO administration? Destination: HeadingBPH_17474bph17474-sec-0033 Item: Title: 3.2 | Pharmacodynamic studies Destination: HeadingBPH_17474bph17474-sec-0034 Children: Item: Title: 3.2.1 | PD study 1: Does HBB reduce the contractile response of the CUB smooth muscles of rats pre‐stimulated with carbachol? Destination: HeadingBPH_17474bph17474-sec-0035 Item: Title: 3.2.2 | PD study 2: Do the CUB smooth muscles from rats, pre‐incubated with HBB at the same concentration found in the PK... Destination: HeadingBPH_17474bph17474-sec-0036 Item: Title: 3.2.3 | PD study‐3: Do the CUB smooth muscles from rats administered HBB by IV or PO routes present a reduced contractile... Destination: HeadingBPH_17474bph17474-sec-0037 Item: Title: 4 | DISCUSSION Destination: HeadingBPH_17474bph17474-sec-0038 Children: Item: Title: 4.1 | Pharmacokinetic analysis Destination: HeadingBPH_17474bph17474-sec-0039 Item: Title: 4.2 | Pharmacodynamic analysis Destination: HeadingBPH_17474bph17474-sec-0040 Item: Title: 4.3 | Pharmacokinetic/pharmacodynamic modelling Destination: HeadingBPH_17474bph17474-sec-0041 Item: Title: AUTHOR CONTRIBUTIONS Destination: HeadingBPH_17474bph17474-sec-0042 Item: Title: ACKNOWLEDGEMENTS Destination: HeadingBPH_17474bph17474-sec-0043 Item: Title: CONFLICT OF INTEREST STATEMENT Destination: HeadingBPH_17474bph17474-sec-0044 Item: Title: DATA AVAILABILITY STATEMENT Destination: HeadingBPH_17474bph17474-sec-0047 Item: Title: DECLARATION OF TRANSPARENCY AND SCIENTIFIC RIGOUR Destination: HeadingBPH_17474bph17474-sec-0045 Item: Title: ORCID Destination: HeadingBPH_17474ORCid Item: Title: REFERENCES Destination: HeadingBPH_17474bph17474-bibl-00011 Item: Title: SUPPORTING INFORMATION Destination: HeadingBPH_17474SUPPid Filters: FilterPipeline: FlateDecode FilterPipeline: DCTDecode Images: Image: NisoImageMetadata: FormatName: image/png ImageWidth: 228 ImageHeight: 45 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/png ImageWidth: 228 ImageHeight: 45 ColorSpace: black is zero BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/png ImageWidth: 2095 ImageHeight: 2079 BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 1378 ImageHeight: 1794 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/png ImageWidth: 1378 ImageHeight: 694 BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/png ImageWidth: 2095 ImageHeight: 1886 BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/png ImageWidth: 2095 ImageHeight: 1893 BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 83 ImageHeight: 83 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 71 ImageHeight: 68 BitsPerSample: 8 BitsPerSampleUnit: integer Intent: Perceptual Fonts: Type1: Font: BaseFont: ECOKOG+AdvTTa9c1b374+20 FontSubset: true FirstChar: 129 LastChar: 151 FontDescriptor: FontName: ECOKOG+AdvTTa9c1b374+20 Flags: Nonsymbolic FontBBox: -239, -218, 1166, 937 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECPKMO+AdvOT8608a8d1+22 FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: ECPKMO+AdvOT8608a8d1+22 Flags: Symbolic FontBBox: 0, -322, 1218, 968 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ECOKOH+AdvP4C4E74 FontSubset: true FirstChar: 1 LastChar: 254 FontDescriptor: FontName: ECOKOH+AdvP4C4E74 Flags: Symbolic FontBBox: -20, -958, 1114, 770 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ECOKOI+AdvTTeb5f0e55.I FontSubset: true FirstChar: 38 LastChar: 122 FontDescriptor: FontName: ECOKOI+AdvTTeb5f0e55.I Flags: Nonsymbolic FontBBox: -83, -177, 989, 927 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECOLND+AdvP4C4E59 FontSubset: true FirstChar: 2 LastChar: 61 FontDescriptor: FontName: ECOLND+AdvP4C4E59 Flags: Symbolic FontBBox: -31, -250, 1000, 750 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: EDBHEC+AdvTTa9c1b374+03 FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: EDBHEC+AdvTTa9c1b374+03 Flags: Symbolic FontBBox: -500, -260, 1041, 947 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: EDBJND+AdvOT8608a8d1 FontSubset: true FirstChar: 34 LastChar: 34 FontDescriptor: FontName: EDBJND+AdvOT8608a8d1 Flags: Nonsymbolic FontBBox: -62, -208, 927, 958 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECONCP+AdvP4C4E46 FontSubset: true FirstChar: 1 LastChar: 3 FontDescriptor: FontName: ECONCP+AdvP4C4E46 Flags: Symbolic FontBBox: 207, -2359, 700, 40 FontFile3: true EncodingDictionary: Differences: true Font: BaseFont: ECONLN+AdvOT8608a8d1+20 FontSubset: true FirstChar: 146 LastChar: 148 FontDescriptor: FontName: ECONLN+AdvOT8608a8d1+20 Flags: Nonsymbolic FontBBox: -968, -333, 2000, 1020 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECONCO+AdvOT8608a8d1+03 FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: ECONCO+AdvOT8608a8d1+03 Flags: Symbolic FontBBox: -479, -364, 854, 927 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ECPHMA+AdvTTfac587ca.B FontSubset: true FirstChar: 49 LastChar: 85 FontDescriptor: FontName: ECPHMA+AdvTTfac587ca.B Flags: Nonsymbolic FontBBox: -72, -177, 1062, 958 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECOLNE+AdvTTa9c1b374+01 FontSubset: true FirstChar: 1 LastChar: 154 FontDescriptor: FontName: ECOLNE+AdvTTa9c1b374+01 Flags: Symbolic FontBBox: -62, -187, 1333, 1052 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ECOLNF+AdvTT0459e7ca.B FontSubset: true FirstChar: 63 LastChar: 121 FontDescriptor: FontName: ECOLNF+AdvTT0459e7ca.B Flags: Nonsymbolic FontBBox: -62, -177, 1041, 947 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECOKMF+AdvTT6071803a.B FontSubset: true FirstChar: 40 LastChar: 124 FontDescriptor: FontName: ECOKMF+AdvTT6071803a.B Flags: Nonsymbolic FontBBox: -52, -177, 1041, 947 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECOKOF+AdvTTa9c1b374 FontSubset: true FirstChar: 35 LastChar: 252 FontDescriptor: FontName: ECOKOF+AdvTTa9c1b374 Flags: Nonsymbolic FontBBox: -41, -177, 1010, 927 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: ECPKMP+AdvTT9c438aa4.BI FontSubset: true FirstChar: 67 LastChar: 121 FontDescriptor: FontName: ECPKMP+AdvTT9c438aa4.BI Flags: Nonsymbolic FontBBox: -83, -177, 1010, 947 FontFile3: true Encoding: WinAnsiEncoding XMP: application/pdfdoi:10.1111/bph.17474 10.1111/bph.17474https://doi.org/10.1111/bph.17474 2025-02-13truebpspubs.onlinelibrary.wiley.com10.1111/bph.17474 bpspubs.onlinelibrary.wiley.comtrue10.1111/bph.174742025-02-13 VoR Pages: Page: Label: 2487 Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 115, 592, 116, 604 Destination: 417 Annotation: Subtype: Link Rect: 115, 597, 121, 610 Destination: 417 Annotation: Subtype: Link Rect: 251, 592, 252, 604 Destination: 417 Annotation: Subtype: Link Rect: 251, 597, 258, 610 Destination: 417 Annotation: Subtype: Link Rect: 356, 592, 357, 604 Destination: 417 Annotation: Subtype: Link Rect: 356, 597, 362, 610 Destination: 417 Annotation: Subtype: Link Rect: 469, 592, 470, 604 Destination: 417 Annotation: Subtype: Link Rect: 469, 597, 483, 610 Destination: 417 Annotation: Subtype: Link Rect: 128, 574, 129, 586 Destination: 417 Annotation: Subtype: Link Rect: 128, 579, 134, 591 Destination: 417 Annotation: Subtype: Link Rect: 137, 578, 145, 586 Annotation: Subtype: Link Rect: 65, 329, 136, 336 Annotation: Subtype: Link Rect: 45, 730, 124, 737 Annotation: Subtype: Link Rect: 205, 62, 298, 69 Annotation: Subtype: Link Rect: 411, 22, 518, 29 Annotation: Subtype: Link Rect: 519, 782, 595, 767 Thumb: true Page: Label: 2488 Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 68, 669, 86, 677 Destination: 289 Annotation: Subtype: Link Rect: 205, 643, 224, 651 Destination: 326 Annotation: Subtype: Link Rect: 133, 630, 171, 638 Annotation: Subtype: Link Rect: 129, 604, 147, 612 Destination: 289 Annotation: Subtype: Link Rect: 205, 604, 223, 612 Destination: 289 Annotation: Subtype: Link Rect: 277, 590, 288, 598 Annotation: Subtype: Link Rect: 64, 577, 75, 585 Annotation: Subtype: Link Rect: 206, 578, 253, 586 Annotation: Subtype: Link Rect: 100, 552, 118, 560 Destination: 289 Annotation: Subtype: Link Rect: 73, 513, 92, 521 Destination: 326 Annotation: Subtype: Link Rect: 160, 513, 178, 521 Destination: 326 Annotation: Subtype: Link Rect: 211, 513, 230, 521 Destination: 326 Annotation: Subtype: Link Rect: 236, 487, 254, 495 Destination: 289 Annotation: Subtype: Link Rect: 67, 474, 85, 482 Destination: 289 Annotation: Subtype: Link Rect: 158, 409, 177, 417 Destination: 326 Annotation: Subtype: Link Rect: 229, 344, 260, 352 Annotation: Subtype: Link Rect: 66, 305, 84, 313 Destination: 289 Annotation: Subtype: Link Rect: 136, 305, 155, 313 Destination: 326 Annotation: Subtype: Link Rect: 196, 305, 215, 313 Destination: 374 Annotation: Subtype: Link Rect: 222, 136, 240, 144 Destination: 326 Annotation: Subtype: Link Rect: 66, 110, 84, 118 Destination: 326 Annotation: Subtype: Link Rect: 179, 97, 249, 105 Thumb: true Page: Label: 2489 Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 516, 539, 533, 547 Destination: 101 Annotation: Subtype: Link Rect: 306, 526, 324, 534 Destination: 101 Annotation: Subtype: Link Rect: 529, 396, 549, 404 Annotation: Subtype: Link Rect: 306, 383, 356, 391 Thumb: true Page: Label: 2490 Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 216, 669, 286, 677 Annotation: Subtype: Link Rect: 135, 630, 152, 638 Destination: 101 Annotation: Subtype: Link Rect: 45, 617, 79, 625 Annotation: Subtype: Link Rect: 82, 487, 87, 495 Destination: 109 Annotation: Subtype: Link Rect: 221, 344, 226, 352 Destination: 109 Annotation: Subtype: Link Rect: 131, 201, 140, 209 Destination: 374 Annotation: Subtype: Link Rect: 413, 578, 482, 586 Annotation: Subtype: Link Rect: 343, 539, 360, 547 Destination: 101 Annotation: Subtype: Link Rect: 408, 344, 413, 352 Destination: 109 Annotation: Subtype: Link Rect: 444, 227, 513, 235 Annotation: Subtype: Link Rect: 336, 175, 354, 183 Destination: 54 Thumb: true Page: Label: 2491 Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 150, 708, 167, 716 Destination: 101 Annotation: Subtype: Link Rect: 237, 539, 242, 547 Destination: 133 Annotation: Subtype: Link Rect: 266, 97, 284, 105 Destination: 289 Annotation: Subtype: Link Rect: 376, 474, 404, 482 Annotation: Subtype: Link Rect: 498, 474, 526, 482 Annotation: Subtype: Link Rect: 321, 448, 354, 456 Annotation: Subtype: Link Rect: 400, 370, 532, 378 Annotation: Subtype: Link Rect: 460, 344, 478, 352 Destination: 289 Annotation: Subtype: Link Rect: 327, 331, 345, 339 Destination: 289 Annotation: Subtype: Link Rect: 332, 201, 336, 209 Destination: 148 Annotation: Subtype: Link Rect: 494, 149, 498, 157 Destination: 156 Thumb: true Page: Label: 2492 Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 419, 123, 428, 131 Destination: 374 Annotation: Subtype: Link Rect: 473, 123, 478, 131 Destination: 148 Thumb: true Page: Label: 2493 Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 222, 149, 227, 157 Destination: 176 Annotation: Subtype: Link Rect: 176, 71, 185, 79 Destination: 374 Annotation: Subtype: Link Rect: 364, 253, 368, 261 Destination: 176 Annotation: Subtype: Link Rect: 406, 253, 411, 261 Destination: 184 Annotation: Subtype: Link Rect: 395, 240, 404, 248 Destination: 176 Annotation: Subtype: Link Rect: 332, 84, 341, 92 Destination: 176 Annotation: Subtype: Link Rect: 267, 674, 269, 682 Destination: 156 Annotation: Subtype: Link Rect: 282, 646, 285, 654 Destination: 156 Annotation: Subtype: Link Rect: 263, 604, 265, 612 Destination: 156 Annotation: Subtype: Link Rect: 278, 576, 281, 584 Destination: 156 Annotation: Subtype: Link Rect: 263, 534, 265, 542 Destination: 156 Annotation: Subtype: Link Rect: 278, 506, 281, 514 Destination: 156 Annotation: Subtype: Link Rect: 263, 464, 265, 472 Destination: 156 Annotation: Subtype: Link Rect: 278, 436, 281, 444 Destination: 156 Thumb: true Page: Label: 2494 Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 512, 655, 517, 663 Destination: 109 Annotation: Subtype: Link Rect: 428, 633, 432, 641 Destination: 109 Thumb: true Page: Label: 2495 Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 92, 318, 100, 326 Destination: 176 Annotation: Subtype: Link Rect: 69, 123, 73, 131 Destination: 156 Annotation: Subtype: Link Rect: 193, 123, 198, 131 Destination: 203 Annotation: Subtype: Link Rect: 237, 123, 242, 131 Destination: 184 Annotation: Subtype: Link Rect: 377, 136, 381, 144 Destination: 211 Annotation: Subtype: Link Rect: 419, 136, 424, 144 Destination: 184 Annotation: Subtype: Link Rect: 439, 696, 442, 704 Destination: 184 Annotation: Subtype: Link Rect: 180, 679, 183, 687 Destination: 184 Annotation: Subtype: Link Rect: 263, 679, 266, 687 Destination: 184 Annotation: Subtype: Link Rect: 346, 679, 349, 687 Destination: 184 Annotation: Subtype: Link Rect: 443, 679, 446, 687 Destination: 184 Annotation: Subtype: Link Rect: 526, 679, 528, 687 Destination: 184 Annotation: Subtype: Link Rect: 428, 552, 431, 560 Destination: 184 Annotation: Subtype: Link Rect: 428, 538, 431, 546 Destination: 184 Annotation: Subtype: Link Rect: 253, 468, 256, 476 Destination: 184 Thumb: true Page: Label: 2496 Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 82, 110, 86, 118 Destination: 184 Annotation: Subtype: Link Rect: 68, 233, 73, 241 Destination: 156 Annotation: Subtype: Link Rect: 269, 222, 273, 230 Destination: 133 Thumb: true Page: Label: 2497 Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 77, 71, 95, 79 Destination: 374 Annotation: Subtype: Link Rect: 71, 45, 89, 53 Destination: 326 Annotation: Subtype: Link Rect: 529, 110, 547, 118 Destination: 326 Annotation: Subtype: Link Rect: 339, 97, 357, 105 Destination: 326 Annotation: Subtype: Link Rect: 387, 97, 406, 105 Destination: 374 Annotation: Subtype: Link Rect: 434, 45, 452, 53 Destination: 326 Annotation: Subtype: Link Rect: 516, 45, 534, 53 Destination: 289 Annotation: Subtype: Link Rect: 537, 220, 541, 228 Destination: 133 Thumb: true Page: Label: 2498 Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 70, 695, 88, 703 Destination: 326 Annotation: Subtype: Link Rect: 128, 695, 147, 703 Destination: 326 Annotation: Subtype: Link Rect: 198, 695, 217, 703 Destination: 374 Annotation: Subtype: Link Rect: 266, 630, 284, 638 Destination: 374 Annotation: Subtype: Link Rect: 98, 591, 116, 599 Destination: 289 Annotation: Subtype: Link Rect: 146, 591, 164, 599 Destination: 326 Annotation: Subtype: Link Rect: 147, 539, 165, 547 Destination: 326 Annotation: Subtype: Link Rect: 188, 513, 206, 521 Destination: 326 Annotation: Subtype: Link Rect: 80, 396, 98, 404 Destination: 326 Annotation: Subtype: Link Rect: 69, 175, 87, 183 Destination: 326 Annotation: Subtype: Link Rect: 120, 175, 138, 183 Destination: 326 Annotation: Subtype: Link Rect: 128, 136, 146, 144 Destination: 326 Annotation: Subtype: Link Rect: 448, 578, 467, 586 Destination: 326 Annotation: Subtype: Link Rect: 505, 552, 524, 560 Destination: 374 Annotation: Subtype: Link Rect: 327, 539, 345, 547 Destination: 374 Annotation: Subtype: Link Rect: 456, 513, 474, 521 Destination: 326 Annotation: Subtype: Link Rect: 476, 474, 494, 482 Destination: 326 Annotation: Subtype: Link Rect: 365, 435, 383, 443 Destination: 326 Annotation: Subtype: Link Rect: 389, 409, 408, 417 Destination: 326 Annotation: Subtype: Link Rect: 474, 409, 493, 417 Destination: 326 Annotation: Subtype: Link Rect: 482, 318, 500, 326 Destination: 289 Annotation: Subtype: Link Rect: 529, 292, 547, 300 Destination: 326 Annotation: Subtype: Link Rect: 385, 279, 403, 287 Destination: 374 Annotation: Subtype: Link Rect: 445, 279, 463, 287 Destination: 374 Annotation: Subtype: Link Rect: 329, 240, 347, 248 Destination: 289 Annotation: Subtype: Link Rect: 396, 240, 414, 248 Destination: 374 Annotation: Subtype: Link Rect: 465, 240, 484, 248 Destination: 374 Annotation: Subtype: Link Rect: 527, 214, 545, 222 Destination: 374 Annotation: Subtype: Link Rect: 479, 201, 510, 209 Annotation: Subtype: Link Rect: 376, 188, 394, 196 Destination: 326 Annotation: Subtype: Link Rect: 494, 84, 512, 92 Destination: 374 Annotation: Subtype: Link Rect: 438, 58, 456, 66 Destination: 289 Thumb: true Page: Label: 2499 Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 102, 708, 120, 716 Destination: 326 Annotation: Subtype: Link Rect: 198, 682, 217, 690 Destination: 326 Annotation: Subtype: Link Rect: 266, 682, 284, 690 Destination: 326 Annotation: Subtype: Link Rect: 227, 656, 245, 664 Destination: 289 Annotation: Subtype: Link Rect: 66, 552, 84, 560 Destination: 289 Annotation: Subtype: Link Rect: 221, 461, 240, 469 Destination: 326 Annotation: Subtype: Link Rect: 268, 422, 286, 430 Destination: 326 Annotation: Subtype: Link Rect: 91, 409, 109, 417 Destination: 326 Annotation: Subtype: Link Rect: 157, 409, 176, 417 Destination: 374 Annotation: Subtype: Link Rect: 130, 305, 149, 313 Destination: 326 Annotation: Subtype: Link Rect: 69, 279, 73, 287 Destination: 184 Annotation: Subtype: Link Rect: 266, 58, 284, 66 Destination: 326 Annotation: Subtype: Link Rect: 182, 45, 251, 53 Annotation: Subtype: Link Rect: 394, 708, 412, 716 Destination: 289 Annotation: Subtype: Link Rect: 363, 669, 449, 677 Annotation: Subtype: Link Rect: 340, 656, 359, 664 Destination: 289 Annotation: Subtype: Link Rect: 377, 578, 395, 586 Destination: 289 Annotation: Subtype: Link Rect: 432, 578, 450, 586 Destination: 326 Annotation: Subtype: Link Rect: 361, 565, 379, 573 Destination: 326 Annotation: Subtype: Link Rect: 327, 526, 346, 534 Destination: 326 Thumb: true Page: Label: 2500 Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 200, 383, 271, 391 Annotation: Subtype: Link Rect: 45, 370, 130, 378 Annotation: Subtype: Link Rect: 98, 320, 106, 328 Annotation: Subtype: Link Rect: 108, 318, 251, 326 Annotation: Subtype: Link Rect: 206, 248, 288, 255 Annotation: Subtype: Link Rect: 58, 237, 119, 245 Annotation: Subtype: Link Rect: 58, 174, 189, 182 Annotation: Subtype: Link Rect: 192, 101, 288, 108 Annotation: Subtype: Link Rect: 58, 90, 80, 98 Annotation: Subtype: Link Rect: 319, 701, 437, 708 Annotation: Subtype: Link Rect: 443, 679, 549, 687 Annotation: Subtype: Link Rect: 319, 668, 378, 676 Annotation: Subtype: Link Rect: 430, 626, 549, 634 Annotation: Subtype: Link Rect: 319, 616, 360, 623 Annotation: Subtype: Link Rect: 319, 543, 463, 550 Annotation: Subtype: Link Rect: 487, 511, 549, 518 Annotation: Subtype: Link Rect: 319, 500, 424, 508 Annotation: Subtype: Link Rect: 336, 447, 483, 455 Annotation: Subtype: Link Rect: 512, 416, 549, 424 Annotation: Subtype: Link Rect: 319, 405, 402, 413 Annotation: Subtype: Link Rect: 319, 332, 437, 339 Annotation: Subtype: Link Rect: 430, 280, 547, 287 Annotation: Subtype: Link Rect: 498, 226, 549, 234 Annotation: Subtype: Link Rect: 319, 216, 406, 223 Annotation: Subtype: Link Rect: 451, 163, 549, 171 Annotation: Subtype: Link Rect: 319, 153, 388, 161 Annotation: Subtype: Link Rect: 512, 122, 549, 129 Annotation: Subtype: Link Rect: 319, 111, 413, 118 Annotation: Subtype: Link Rect: 436, 79, 549, 87 Annotation: Subtype: Link Rect: 319, 69, 369, 76 Thumb: true Page: Label: 2501 Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 123, 701, 252, 708 Annotation: Subtype: Link Rect: 182, 648, 288, 655 Annotation: Subtype: Link Rect: 58, 637, 100, 645 Annotation: Subtype: Link Rect: 137, 596, 276, 603 Annotation: Subtype: Link Rect: 160, 554, 277, 561 Annotation: Subtype: Link Rect: 75, 511, 246, 519 Annotation: Subtype: Link Rect: 99, 469, 263, 477 Annotation: Subtype: Link Rect: 58, 406, 208, 414 Annotation: Subtype: Link Rect: 58, 354, 229, 361 Annotation: Subtype: Link Rect: 206, 333, 288, 341 Annotation: Subtype: Link Rect: 58, 322, 131, 330 Annotation: Subtype: Link Rect: 226, 280, 288, 288 Annotation: Subtype: Link Rect: 58, 270, 116, 277 Annotation: Subtype: Link Rect: 151, 228, 288, 235 Annotation: Subtype: Link Rect: 58, 217, 84, 225 Annotation: Subtype: Link Rect: 192, 154, 288, 162 Annotation: Subtype: Link Rect: 58, 144, 80, 151 Annotation: Subtype: Link Rect: 206, 112, 288, 120 Annotation: Subtype: Link Rect: 58, 102, 97, 109 Annotation: Subtype: Link Rect: 58, 60, 180, 67 Annotation: Subtype: Link Rect: 524, 701, 549, 708 Annotation: Subtype: Link Rect: 319, 690, 425, 698 Annotation: Subtype: Link Rect: 394, 669, 529, 676 Annotation: Subtype: Link Rect: 391, 627, 512, 634 Annotation: Subtype: Link Rect: 463, 596, 549, 603 Annotation: Subtype: Link Rect: 319, 585, 411, 593 Annotation: Subtype: Link Rect: 487, 543, 549, 550 Annotation: Subtype: Link Rect: 319, 532, 435, 540 Annotation: Subtype: Link Rect: 467, 469, 549, 477 Annotation: Subtype: Link Rect: 319, 459, 387, 466 Annotation: Subtype: Link Rect: 487, 427, 549, 435 Annotation: Subtype: Link Rect: 319, 417, 435, 424 Annotation: Subtype: Link Rect: 319, 333, 473, 341 Annotation: Subtype: Link Rect: 439, 270, 549, 277 Annotation: Subtype: Link Rect: 319, 259, 359, 267 Annotation: Subtype: Link Rect: 374, 207, 515, 214 Annotation: Subtype: Link Rect: 353, 175, 475, 183 Annotation: Subtype: Link Rect: 458, 154, 549, 162 Annotation: Subtype: Link Rect: 319, 144, 431, 151 Annotation: Subtype: Link Rect: 463, 70, 549, 78 Annotation: Subtype: Link Rect: 319, 60, 383, 67 Thumb: true Page: Label: 2502 Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 237, 701, 288, 708 Annotation: Subtype: Link Rect: 58, 690, 184, 698 Annotation: Subtype: Link Rect: 135, 648, 263, 655 Annotation: Subtype: Link Rect: 163, 596, 288, 603 Annotation: Subtype: Link Rect: 58, 585, 82, 593 Annotation: Subtype: Link Rect: 182, 511, 288, 519 Annotation: Subtype: Link Rect: 58, 501, 123, 508 Annotation: Subtype: Link Rect: 161, 449, 288, 456 Annotation: Subtype: Link Rect: 58, 438, 84, 446 Annotation: Subtype: Link Rect: 58, 406, 241, 414 Annotation: Subtype: Link Rect: 463, 679, 549, 687 Annotation: Subtype: Link Rect: 319, 669, 383, 676 Annotation: Subtype: Link Rect: 524, 637, 549, 645 Annotation: Subtype: Link Rect: 319, 627, 464, 634 Annotation: Subtype: Link Rect: 487, 574, 549, 582 Annotation: Subtype: Link Rect: 319, 564, 407, 571 Annotation: Subtype: Link Rect: 512, 522, 549, 529 Annotation: Subtype: Link Rect: 319, 511, 432, 519 Annotation: Subtype: Link Rect: 446, 368, 533, 376 Annotation: Subtype: Link Rect: 319, 355, 357, 363 Thumb: true Checksum: 7d484b4e Type: CRC32 Checksum: 4fd0726199dc7db7a47a6c07f2937e06 Type: MD5 Checksum: 6999be08f3cb24cf5cb381d0b78df46f5e701c92 Type: SHA-1 Checksum: c86e2ee2f0f01607a3589b2e3f6994d328f9900c2a3a62ca480b849bfb340d19 Type: SHA-256