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Nyberg, Fred
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Publications (10 of 139) Show all publications
Lesniak, A., Aarnio, M., Diwakarla, S., Norberg, T., Nyberg, F. & Gordh, T. (2018). Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.. Life Sciences, 194, 26-33
Open this publication in new window or tab >>Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
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2018 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 194, p. 26-33Article in journal (Refereed) Published
Abstract [en]

Aims: D-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for D-deprenyl in synovial membrane explants from arthritic patients.

Main methods: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [H-3]D-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation.

Key findings: The [H-3]D-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [H-3]D-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [H-3]D-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [H-3]D-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation.

Significance: Our study was the first to show the biochemical characteristics of the [H-3]D-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.

Keywords
Arthritis, Binding target, Monoamine oxidase B, Synovium, d-Deprenyl
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Biochemistry; Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-347601 (URN)10.1016/j.lfs.2017.12.003 (DOI)000425052000004 ()29221756 (PubMedID)
Funder
Swedish Research Council, 9459
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-18Bibliographically approved
Brolin, E., Zelleroth, S., Jonsson, A., Hallberg, M., Gröndbladh, A. & Nyberg, F. (2018). Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat. Pharmacology, Biochemistry and Behavior, 167, 1-8
Open this publication in new window or tab >>Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
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2018 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 167, p. 1-8Article in journal (Refereed) Published
Abstract [en]

The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2018
Keywords
Morphine, Morris water maze (MWM), Mini-osmotic pumps, Memory, Insulin-like growth factor-1 (IGF-1), N-methyl-D-aspartate (NMDA), Rats
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-352711 (URN)10.1016/j.pbb.2018.01.007 (DOI)000430033600001 ()29421366 (PubMedID)
Funder
Swedish Research Council, 9459Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-06-07Bibliographically approved
Skogh, A., Lesniak, A., Gaugaz, F. Z., Svensson, R., Lindeberg, G., Fransson, R., . . . Sandström, A. (2017). Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration. European Journal of Pharmaceutical Sciences, 109, 533-540, Article ID S0928-0987(17)30497-9.
Open this publication in new window or tab >>Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration
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2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 109, p. 533-540, article id S0928-0987(17)30497-9Article in journal (Refereed) Published
Abstract [en]

Substance P 1-7 (SP1-7, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7) is the major bioactive metabolite formed after proteolytic degradation of the tachykinin substance P (SP). This heptapeptide often opposes the effects of the mother peptide. Hence, SP1-7 is having anti-inflammatory, anti-nociceptive and anti-hyperalgesic effects in experimental models. Despite all encouraging properties of SP1-7 its exact mode of action has not yet been elucidated which has hampered further development of this heptapeptide in drug discovery. Contrary to SP that mediates its biological activity via the NK-1 receptor, the N-terminal fragment SP1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP1-7 amide 1 (Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-NH2) was previously shown to be superior to the endogenous SP1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N-methylation scan of the backbone of the SP1-7 amide (1) results in peptides that are significantly less prone to undergo proteolysis in plasma from both mouse and human. However, with the two exceptions of the [MeLys3]SP1-7 amide (3) and the [MeGln5]SP1-7 amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain. It is suggested that the N-methylation does not allow these peptides to form the accurate bioactive conformations or interactions required for efficient binding to the macromolecular target. The importance of intact N-terminal Arg1 and C-terminal Phe7, anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP1-7 amide (1), the [MeLys3]SP1-7 amide (3) amide and the [MeGln5]SP1-7 amide (4) are all considerably more effective in the SNI mouse model than gabapentin that is widely used in the clinic for treatment of neuropathic pain.

Keywords
Anti-allodynia, N-methylation, SP(1–7) amide, Solid phase peptide synthesis (SPPS), Spared nerve injury (SNI), Substance P (SP)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-335651 (URN)10.1016/j.ejps.2017.09.007 (DOI)000413325000055 ()28887235 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain FoundationBerzelii Centre EXSELENT
Available from: 2017-12-07 Created: 2017-12-07 Last updated: 2018-02-28
Skogh, A., Lesniak, A., Gaugaz, F. Z., Svensson, R., Lindeberg, G., Fransson, R., . . . Sandström, A. (2017). Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration. European Journal of Pharmaceutical Sciences, 106, 345-351
Open this publication in new window or tab >>Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration
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2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 106, p. 345-351Article in journal (Refereed) Published
Abstract [en]

The heptapeptide SP1-7 (1, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)) is the major bioactive metabolite formed after proteolytic processing of the neuropeptide substance P (SP, Arg(1)-Pro(2)-Lys(3)-Pro(4)-GIn(5)-Gln(6)-Phe(7)-Phe(8)-Gly(9)-Leu(10)-Meti(11)-NH2). The heptapeptide 1 frequently exhibits opposite effects to those induced by SP, such as exerting antinociception, or attenuating thermal hyperalgesia and mechanical allodynia. The heptapeptide SP1-7 amide (2, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)-NH2 ) is often more efficacious than 1 in experimental pain models. We have now assessed the anti-allodynic outcome after systemic administration of 2 and a series of Ala substituted and truncated analogues of 2, in the spared nerve injury (SNI) mice model and the results obtained were correlated with in vitro plasma stability and permeability measurements. It is herein demonstrated that an intact Arg(1) in SP1-7 amide analogues is fundamental for retaining a potent in vivo effect, while Lys(3) of 2 is less important. A displacement with Ala(1) or truncation rendered the peptide analogues either inactive or with a significantly attenuated in vivo activity. Thus, the pentapeptide SP3-7 amide (7, t(1/2) = 11.1 min) proven to be the major metabolite of 2, demonstrated an in vivo effect itself although considerably less significant than 2 in the SNI model. Intraperitoneal administration of 2 in a low dose furnished the most powerful anti-allodynic effect in the SNI model of all the analogous evaluated, despite a fast proteolysis of 2 in plasma (t(1/2) = 6.4 min). It is concluded that not only the C-terminal residue, that we previously demonstrated, but also the N-terminal with its basic side chain, are important for achieving effective pain relief. This information is of value for the further design process aimed at identifying more drug-like SP1-7 amide related peptidomimetics with pronounced antiallodynic effects.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Neuropathic pain, Spared nerve injury (SNI), SP1-7, Neuropeptides, Plasma stability, Structure-activity relationship, Message-address concept
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-334033 (URN)10.1016/j.ejps.2017.06.004 (DOI)000406988600036 ()28587787 (PubMedID)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-02-28Bibliographically approved
Brolin, E., Johansson, J., Zelleroth, S., Diwakarla, S., Nyberg, F., Gröndbladh, A. & Hallberg, M. (2017). The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration. Neuroscience Letters, 646, 15-20
Open this publication in new window or tab >>The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration
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2017 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 646, p. 15-20Article in journal (Refereed) Published
Abstract [en]

In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.

Keywords
Growth hormone, gamma-hydroxybuturate, insulin-like growth factor-1, central nervous system, frontal cortex, cognition
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-317299 (URN)10.1016/j.neulet.2017.02.053 (DOI)000401679600003 ()28249788 (PubMedID)
Funder
Swedish Research Council, 9459Carl Tryggers foundation
Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2018-01-13Bibliographically approved
Dabo Pettersson, F., Hellgren, C., Nyberg, F., Åkerud, H. & Sundström Poromaa, I. (2016). Anxiety, Depressed Mood and the Use of Labor Analgesia. Archives of Women's Mental Health, 19(1), 11-16
Open this publication in new window or tab >>Anxiety, Depressed Mood and the Use of Labor Analgesia
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2016 (English)In: Archives of Women's Mental Health, ISSN 1434-1816, E-ISSN 1435-1102, Vol. 19, no 1, p. 11-16Article in journal (Refereed) Published
Abstract [en]

Relatively little is known about mental health and labor pain. The aim of this study was to assess if self-rated antenatal depressed mood and anxiety are associated with pain-related behaviors and self-reported labor pain. We also wanted to replicate our previous finding of altered labor pain behavior in carriers of a specific guanosine triphosphate cyclohydrolase 1 gene (GCH1) haplotype. Ninety-nine women in gestational weeks 37 to 40 filled out questionnaires on depression and anxiety symptoms and later rated their labor pain by use of visual analog scales. Each subject was also genotyped for GCH1. Following adjustment for relevant confounders, women who arrived early to the delivery unit (cervical dilation < 5 cm) had a significantly higher antenatal Montgomery-sberg Depression Rating Scale (MADRS-S) score, p < 0.05, than late arrivers (cervical dilation > 5 cm). Women with increased Spielberger State-Trait Anxiety Inventory (STAI-T) scores reported higher self-rated pain prior to labor analgesia, p < 0.05, than women with low STAI-T scores. No association between the GCH1 pain-protective haplotype and cervical dilation was found, but a previously demonstrated association with increased use of second-line analgesia was confirmed. Depressed mood during pregnancy is associated with early arrival to the delivery department, whereas antenatal anxiety is associated with increased self-rated pain prior to labor analgesia.

Keywords
anxiety, depression, GCH1, labor pain
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-162544 (URN)10.1007/s00737-015-0572-6 (DOI)000369012400003 ()26392364 (PubMedID)
Projects
Genetics and Labor Pain Behavior
Available from: 2011-12-01 Created: 2011-12-01 Last updated: 2017-12-08Bibliographically approved
Lai, Z., Yin, H., Cabrera-Perez, J., Guimaro, M. C., Afione, S., Michael, D. G., . . . Chiorini, J. A. (2016). Aquaporin gene therapy corrects Sjogren's syndrome phenotype in mice. Proceedings of the National Academy of Sciences of the United States of America, 113(20), 5694-5699
Open this publication in new window or tab >>Aquaporin gene therapy corrects Sjogren's syndrome phenotype in mice
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 20, p. 5694-5699Article in journal (Refereed) Published
Abstract [en]

Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjogren's syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjogren's syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjogren's syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjogren's syndrome.

Keywords
aquaporin, gene therapy, Sjogren's syndrome
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-297780 (URN)10.1073/pnas.1601992113 (DOI)000375977600059 ()27140635 (PubMedID)
Funder
NIH (National Institute of Health)NIH (National Institute of Health), DE023433NIH (National Institute of Health), DE018958
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2018-01-10Bibliographically approved
Nehlin, C., Nyberg, F. & Jess, K. (2016). Brief Intervention Within Primary Care for At-Risk Gambling: A Pilot Study. Journal of Gambling Studies, 32(4), 1327-1335
Open this publication in new window or tab >>Brief Intervention Within Primary Care for At-Risk Gambling: A Pilot Study
2016 (English)In: Journal of Gambling Studies, ISSN 1050-5350, E-ISSN 1573-3602, Vol. 32, no 4, p. 1327-1335Article in journal (Refereed) Published
Abstract [en]

Studies on interventions for at-risk gambling are scarce. This pilot study is the first step in a larger project aimed to develop methods to prevent more serious gambling problems. Drawing on experiences from the alcohol field, the brief intervention (BI) model was tested in a primary care setting. Primary care personnel was trained for 2 days. Patients were screened, and those with signs of problematic gambling were offered a return visit to discuss their gambling habits. Of the 537 screened, 34 (6.3 %) screened positive for problem gambling. Of those, 24 were at-risk gamblers whereof 19 agreed to participate. Six of those 19 took part in a 1-month follow-up. Important information for the planning of upcoming studies was collected from the pilot work. Given that the rate of at-risk gamblers was elevated in this setting we consider primary care a suitable arena for intervention. Staff training and support appeared essential, and questionnaires should be selected that are clear and well-presented so staff feel secure and comfortable with them. The BI model was found to be most suitable for patients already known to the caregiver. The number of participants who were willing to take part in the follow-up was low. To ensure power in future studies, a much larger number of screened patients is evidently necessary.

Keywords
Brief intervention (BI), At-risk gambling, Primary care, Pilot study
National Category
Psychiatry Substance Abuse
Identifiers
urn:nbn:se:uu:diva-310738 (URN)10.1007/s10899-016-9610-1 (DOI)000387615100018 ()27038815 (PubMedID)
Funder
Public Health Agency of Sweden
Available from: 2016-12-20 Created: 2016-12-19 Last updated: 2017-11-29Bibliographically approved
Lai, Z., Grönbladh, A., Hallberg, M. & Nyberg, F. (2016). Effects of growth hormone on brain function: new routes for the delivery of the hormone into the brain. Amino Acids, 48(2), 633-634
Open this publication in new window or tab >>Effects of growth hormone on brain function: new routes for the delivery of the hormone into the brain
2016 (English)In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 48, no 2, p. 633-634Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-282733 (URN)000369307700080 ()
Available from: 2016-06-20 Created: 2016-04-06 Last updated: 2018-01-10Bibliographically approved
Nylander, E., Gröndbladh, A., Zelleroth, S., Diwakarla, S., Nyberg, F. & Hallberg, M. (2016). Growth hormone is protective against acute methadone-induced toxicity by modulating the NMDA receptor complex. Neuroscience, 339, 538-547
Open this publication in new window or tab >>Growth hormone is protective against acute methadone-induced toxicity by modulating the NMDA receptor complex
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2016 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 339, p. 538-547Article in journal (Refereed) Published
Abstract [en]

Human growth hormone (GH) displays promising protective effects in the central nervous system after damage caused by various insults. Current evidence suggests that these effects may involve N-methyl-d-aspartate (NMDA) receptor function, a receptor that also is believed to play a role in opioid-induced neurotoxicity. The aims of the present study were to examine the acute toxic effects of methadone, an opioid receptor agonist and NMDA receptor antagonist, as well as to evaluate the protective properties of recombinant human GH (rhGH) on methadone-induced toxicity. Primary cortical cell cultures from embryonic day 17 rats were grown for 7 days in vitro. Cells were treated with methadone for 24 h and the 50% lethal dose was calculated and later used for protection studies with rhGH. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase release, and caspase activation. Furthermore, the mRNA expression levels of NMDA receptor subunits were investigated following methadone and rhGH treatment using quantitative PCR (qPCR) analysis. A significant protective effect was observed with rhGH treatment on methadone-induced mitochondrial dysfunction and in methadone-induced LDH release. Furthermore, methadone significantly increased caspase-3 and -7 activation but rhGH was unable to inhibit this effect. The mRNA expression of the NMDA receptor subunit GluN1, GluN2a, and GluN2b increased following methadone treatment, as assessed by qPCR, and rhGH treatment effectively normalized this expression to control levels. We have demonstrated that rhGH can rescue cells from methadone-induced toxicity by maintaining mitochondrial function, cellular integrity, and NMDA receptor complex expression.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
growth hormone, methadone, opioids, neuroprotection, NMDA, primary cell culture
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-306727 (URN)10.1016/j.neuroscience.2016.10.019 (DOI)000389168500045 ()27746341 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain Foundation
Available from: 2016-11-03 Created: 2016-11-03 Last updated: 2018-01-13
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