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Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms
© Aman et al. 2016
Received: 15 August 2015
Accepted: 11 February 2016
Published: 24 February 2016
Passiflora incarnata is widely used as an anxiolytic and sedative due to its putative GABAergic properties. Passiflora incarnata L. methanolic extract (PI-ME) was evaluated in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia in rats along with antinociceptive, anxiolytic and sedative activities in mice in order to examine possible underlying mechanisms.
PI-ME was tested preliminary for qualitative phytochemical analysis and then quantitatively by proximate and GC-MS analysis. The antinociceptive property was evaluated using the abdominal constriction assay and hot plate test. The anxiolytic activity was performed in a stair case model and sedative activity in an open field test. The antagonistic activities were evaluated using naloxone and/or pentylenetetrazole (PTZ). PI-ME was evaluated for prospective anti-allodynic and anti-vulvodynic properties in a rat model of streptozotocin induced neuropathic pain using the static and dynamic testing paradigms of mechanical allodynia and vulvodynia.
GC-MS analysis revealed that PI-ME contained predominant quantities of oleamide (9-octadecenamide), palmitic acid (hexadecanoic acid) and 3-hydroxy-dodecanoic acid, among other active constituents. In the abdominal constriction assay and hot plate test, PI-ME produced dose dependant, naloxone and pentylenetetrazole reversible antinociception suggesting an involvement of opioidergic and GABAergic mechanisms. In the stair case test, PI-ME at 200 mg/kg increased the number of steps climbed while at 600 mg/kg a significant decrease was observed. The rearing incidence was diminished by PI-ME at all tested doses and in the open field test, PI-ME decreased locomotor activity to an extent that was analagous to diazepam. The effects of PI-ME were antagonized by PTZ in both the staircase and open field tests implicating GABAergic mechanisms in its anxiolytic and sedative activities. In the streptozotocin-induced neuropathic nociceptive model, PI-ME (200 and 300 mg/kg) exhibited static and dynamic anti-allodynic effects exemplified by an increase in paw withdrawal threshold and paw withdrawal latency. PI-ME relieved only the dynamic component of vulvodynia by increasing flinching response latency.
These findings suggest that Passiflora incarnata might be useful for treating neuropathic pain. The antinociceptive and behavioural findings inferring that its activity may stem from underlying opioidergic and GABAergic mechanisms though a potential oleamide-sourced cannabimimetic involvement is also discussed.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage . The phenomenon of pain may be nociceptive or neuropathic in nature, and caused by damage to non-neural or neuronal tissues respectively [2, 3]. Neuropathic pain is a major cause of morbidity and has a profound impact on patient well-being. It involves the sensation of allodynia; a painful sensation to a normally non-noxious stimulus and hyperalgesia; an exaggerated pain response to a normally noxious stimulus . Neuropathic pain results from various causes that affect the central nervous system including multiple sclerosis, post stroke or spinal cord pain. Alternatively, it may be associated with damage to the peripheral nervous system, for instance, diabetic neuropathy and trigeminal or post-herpetic neuralgia . Management of neuropathic pain poses an enormous challenge due to the restricted efficacy of assorted pharmacotherapies including both natural treatments [6–8] and synthetic medicaments [9, 10] which are limited by the occurrence of side effects and the extent of pain inhibition .
Passiflora incarnata L. (Additional file 1: Figure S1) from the genus Passiflora (family: Passifloraceae) commonly known as Passion flower, is a fast growing perennial vine widely spread in tropical and warm temperate regions . Phytochemical analysis of P. incarnata has demonstrated that flavonoids constitute about 2.5 % of the total phyto-constituents [13, 14] mainly present in the leaves, the greatest concentration of flavonoid being vitexin compared to the other species of its genus [12, 15]. P. incarnata has been studied for its analgesic , anxiolytic [17–20], anticonvulsant , antitussive , aphrodisiac , anti-asthmatic , anti-diabetic and hypolipidemic properties  along with efficacy in the treatment of cannabinoid , morphine , nicotine  and alcohol dependence . Traditionally, P. incarnata has been used for curing various ailments like anxiety, insomnia, convulsions, sexual dysfunction, cough and cancer  and is well known in relieving neuropathic conditions . In this regard, an eye wipe test has been conducted suggesting a potential application in relieving trigeminal neuralgia . Clinical investigations on P. incarnata have indicated effectiveness in the treatment of anxiety [32, 33], insomnia , opioid withdrawal , attention deficit hyperactivity disorder  and postmenopausal symptoms .
Neuropathic pain results from a cascade of neurobiological events that induces electrical hyperexcitability in somatosensory conduction pathways and results in hyperesthesia, dysesthesia, hyperalgesia, paresthesia or allodynia . Currently, the most common choices of therapy for neuropathic pain are tricyclic antidepressants and anticonvulsants [39, 40]. However, these therapies are only partially effective and are usually accompanied by a variety of side effects . The use of complementary and alternative medicine has been shown to produce some beneficial effects in the management of painful neuropathy  and several herbal medicines exhibit promise in different types of experimentally induced neuropathic pain models [6, 8, 43–45]. Thus there is some scope for new herbal medicines to combat neuropathic pain syndromes . The present study was therefore designed to evaluate the ameliorative effect of P. incarnata methanolic extract (PI-ME) in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia  in rodents. Additionally, PI-ME induced antinociceptive, anxiolytic and sedative activities were also investigated using naloxone and pentylenetetrazole (PTZ) to probe its possible underlying mechanisms.
Morphine (Punjab Drug House, Lahore, Pakistan), diclofenac sodium (≥98 %, Continental Chemicals Company Pvt. Ltd. Pakistan), naloxone (98 %, Hangzhou Uniwise International Co., Ltd, China), gabapentin (99 %, MKB Pharmaceuticals Pvt Ltd Peshawar, Pakistan), diazepam (Valium 10 mg/ 2 ml, Roche, Pakistan), pentylenetetrazole (≥98 %, Sigma Aldrich, UK) , streptozotocin (≥98 %, Sigma Aldrich, UK) and commercial grade methanol (Haq Chemicals Ltd Peshawar, Pakistan).
Preparation of Passiflora incarnata methanolic extract
P. incarnata whole plant was collected from the botanical garden of the Department of Pharmacy, University of Peshawar. It was authenticated by Prof. Dr. Mohammad Ibrar of the Department of Botany, University of Peshawar and a specimen was deposited in the herbarium with a voucher number 20062 (PUP). The aerial parts were separated, shade dried, and coarsely powdered (1000 g). It was macerated for 7 days with commercial grade methanol (5 L). The extract was filtered and concentrated under reduced pressure at 60 °C in a rotary evaporator until a semisolid extract containing no methanol was obtained (yield: 31.20 %).
PI-ME was preliminary evaluated by qualitative phytochemical analysis  and was further screened by quantitative analysis of flavonoids, alkaloids, saponins and tannins [48, 49]. It was also subjected to gas chromatography/mass spectrometry (GC/MS) analysis which was carried out on a 6890 N Agilent gas chromatograph coupled to a JMS 600 H JEOL mass spectrometer. The compound mixture was separated on a fused silica capillary SPBI column, 30 m × 0.32 mm, 0.25 μm film thickness, in a temperature program from 50 to 256 °C with a rate of 4 °C/min with 2 min hold. The injector was at 260 °C and the flow rate of the carrier gas, helium was 1 mL/min. The EI mode of the JMS 600 H JEOL mass spectrometer had an ionization voltage of 70 eV, electron emission of 100 μA, ion source temperature of 250 °C and analyzer temperature of 250 °C. Samples were injected manually in split mode and the total elution time was 90 min. MS scanning was performed from m/z 85 to 390. Identification of the active constituents was based on the computer evaluation of mass spectra of the sample through NIST-based AMDIS (automated mass spectral deconvolution and identification software), direct comparison of peaks and retention times with those of standard compounds as well as by following the characteristic fragmentation patterns of the mass spectra of particular classes of compounds.
BALB/c mice (18–26 g) and female Sprague Dawley rats (150-200 g) maintained in a 12 h light/dark cycle at 22 ± 2 °C were used in the experiments. Food and water were provided ad libitum. Experiments on animals were performed in accordance with the UK Animals (Scientific Procedures) Act 1986 and according to the rules and ethics set forth by the Ethical Committee of the Department of Pharmacy, University of Peshawar. Approval for this study was granted with the registration number: 06/EC-14/Pharm (dated: April 06, 2014). The animal control groups used in experiments were given normal saline which was also the vehicle for all the drugs administered throughout all the experiments.
Abdominal constriction assay
Hot plate test
Anxiolytic activity (Staircase test)
BALB/c mice (18–24 g, n = 8 mice per group) of either sex were administered PI-ME (200, 400 and 600 mg/kg, p.o) or diazepam (2 mg/kg, i.p). In the drug combination experiments, PTZ (10 mg/kg, i.p) was administered 30 min prior to drug treatment. The number of rears and steps climbed by each animal was observed for 3 min using the staircase apparatus and the methods described by Simiand and coworkers . A step was considered to be climbed only if the criterion was met whereby an animal placed all four paws on the step.
BALB/c mice (18–26 g, n = 6 mice per group) of either sex were administered with PI-ME (200, 400 and 600 mg/kg, p.o) or diazepam (4 mg/kg, i.p). In the drug combination experiments, PTZ (10 mg/kg, i.p) was administered 30 min prior to drug treatment. Thirty min later, the animals were placed in the recording apparatus with a floor area of 50 × 40 cm divided into four equal quadrants by lines. The number of lines crossed by each animal was recorded for 30 min using a digital camera (Cat’s Eye IR IP Camera, Taiwan) .
Streptozotocin induced neuropathic pain
Induction of mechanical allodynia and vulvodynia
Female Sprague Dawley rats (150– 200 g, n = 6 rats per group) food withdrawn for 16 h were administered streptozotocin (50 mg/kg, i.p) and food was immediately provided. On the 5th day, animals exhibiting random blood glucose levels greater than 270 mg/dl were included in the study . Body weights and blood glucose were measured at specified time periods. The bedding material was frequently changed to avoid any infection due to excessive urination. On the 29th day post streptozotocin administration, animals were transferred to wire mesh cages and acclimatized for 15–45 min. They were then assessed for mechanical allodynia or vulvodynia before and after PI-ME or standard gabapentin administration using the von Frey up-down method .
Animals were divided into five groups. Group I received normal saline and served as control. Group II remained as the streptozotocin positive control group. Group III received a single intraperitoneal dose of gabapentin (75 mg/kg) and served as the standard. Group IV and V were treated with PI-ME at doses of 200 and 300 mg/kg respectively. The therapeutic doses of PI-ME for evaluation in neuropathic pain were selected on the basis of its analgesic, anxiolytic, locomotor and respective antagonistic activities.
Assessment of static and dynamic allodynia
Static allodynia was assessed using a series of von Frey filaments (0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 g), starting with a 2.0 g force applied perpendicularly to the plantar surface of the right hind paw for 5 s or until the animal displayed a withdrawal response (lifting of the paw). Animals responding to 3.63 g force or below were included in the study and 15 g was selected as the cut-off force .
Dynamic allodynia was assessed by lightly stroking the plantar surface of the hind paw with a cotton bud. Lifting or licking the paw was considered as a withdrawal response and the time taken to show a withdrawal reaction was considered as the paw withdrawal latency (PWL). Animals responding to the cotton bud within 8 s were included in the study and 15 s was selected as the cut off time .
Assessment of static and dynamic vulvodynia
Static vulvodynia was assessed by shaving the anogenital area including the mons pubis. A series of von Frey filaments (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1 g), were applied perpendicularly to the mucous membrane of the anogenital region for 4 s starting with a 0.04 g force, until a flinching response occurred. Animals responding to a 0.16 g force or below were included in the study and a 1.0 g force was selected as the cut-off force .
Dynamic vulvodynia was assessed by lightly brushing a cotton bud over the mucous membrane of the anogenital region for 10 s or until a flinching response occurred. Animals showing a flinching response within 5 s were included in the study and 10 s was selected as the cut-off time .
Data were expressed as mean ± SEM. Statistical comparisons were carried out by one way ANOVA followed by Dunnett’s, Bonferroni or Tukey’s multiple comparison tests where appropriate using GraphPad Prism 5 (GraphPad Software Inc. San Diego CA, USA). Statistical significance was deduced at P ≤ 0.05.
Phytochemical analysis of Passiflora incarnata
Preliminary qualitative phytochemical analysis of Passiflora incarnata methanolic extract (PI-ME)
Aqueous solution of PI-ME + 10 % ammonium hydroxide solution
Appearance of yellow coloration
A portion of PI-ME + few drops of Wagner’s reagent
Reddish brown precipitate
A small volume of PI-ME + 1–2 drops of Mayer’s reagent
Creamy or white precipitate
0.5 ml PI-ME + 0.5 ml benedict’s reagent → mixed and boiled for 2 min
Characteristic colored precipitate
1 ml PI-ME + 1 ml Barfoed’s reagent → boiled for 2 min
50 mg PI-ME + 5 ml distilled water + small amount of 5 % ferric chloride solution
Intense green coloration
Tannins and phenolic compounds present
50 mg PI-ME + conc. HCL → heated on water bath for 2 h → resultant hydrolysate filtered → 2 ml hydrolysate + 3 ml chloroform → chloroform layer separated out + 10 % ammonia solution
A small amount of PI-ME → compressed between two pieces of filter paper
Formation of oil spot on filter paper
Fixed oils present
50 mg PI-ME + 20 ml distilled water → shaken for 15 min
Formation of 2 cm thick layer of foam
GC/MS analysis of Passiflora incarnata methanolic extract
1-Pentanol, 2-methyl-, acetate
9-Tetradecen-1-ol, acetate, (E)-
Dodecanoic acid, 3-hydroxy-
n-Hexadecanoic acid; (Palmitic acid)
9-Octadecenamide, (Z)-; (Oleamide)
Pregnane-3,11,20,21-tetrol, cyclic 20,21-(butyl boronate), (3α,5β,11β,20R)-
2H-1-Benzopyran-6-ol, 3,4-dihydro-2,8-dimethyl-2-(4,8,12-trimethyltridecyl)-, [2R-[2R*(4R*,8R*)]]-
Antinociceptive activity of Passiflora incarnata
Abdominal constriction assay (tonic visceral chemically-induced nociception)
Hot plate test (acute phasic thermal nociception)
Anxiolytic-like activity of Passiflora incarnata
Sedative activity of Passiflora incarnata
Effect of Passiflora incarnata on mechanical allodynia and vulvodynia
The antinociceptive activity of P. incarnata methanolic extract (PI-ME) was evaluated in mice using the hot plate test which is suitable for assessing centrally mediated acute phasic nociception  and the acetic acid induced abdominal constriction assay for tonic visceral nociception [58, 59]. Mice were selected as the species of choice in these specific tests because they are manifestly sensitive not only to opioid mediated effects but also to coexistent non-steroidal anti-inflammatory drug (NSAID) activity . What is more, accumulating evidence indicates that GABAergic transmission plays a pivotal role in the inhibitory regulation of the nociceptive process, and the murine abdominal constriction assay as well as the hot plate test both detect dose dependent GABA agonist antinociception in this species [60, 61]. In both tests, diclofenac as a standard anti-inflammatory analgesic and PI-ME produced antinociceptive activity consistent with previous studies [16, 31, 62]. It was notable that the antinociceptive effect of PI-ME was reversed by the opioid- and GABAA- receptor antagonists, naloxone and pentylenetetrazole (PTZ) respectively, suggesting an involvement of opioidergic and GABAergic mechanisms in the mediation of the antinociception. Opioid agonists decrease pain transmission by activating descending nerve fibers from the periaqueductal gray and raphe nuclei supraspinally and also by inhibition of afferent nerve transmission by binding to pre- and postsynaptic opioid receptors within the spinal cord dorsal horn . Furthermore, GABAergic neurons and receptors that are intercalated within the spinal cord and higher brain pathways are important for the origination, transmission, and modification of pain impulses in such a way that alteration of GABA transmission yields antinociception . P. incarnata has been shown to modulate the activity of GABAergic and opioid systems  to produce central analgesic activity as evaluated by a reduced duration of paw licking in neurogenic and inflammatory nociceptive phases in the formalin test . Due to a prevalence of GABA as a non-α-amino acid constituent of P. incarnata extract , several of its pharmacological effects have been ascribed to mediation via the GABA system. These include not only affinity for GABAA but also GABAB receptors in addition to modification of GABA uptake . The antinociceptive effects of both GABAA and GABAB receptor agonists are known to involve activation or inhibition of other neurotransmitter or neuromodulator pathways  and it is evident that central GABAergic systems are involved in opioid-mediated analgesia . Thus, it is possible that administration of GABA receptor agonists in combination with other agents may yield GABA receptor-related therapies for the treatment of acute and chronic pain .
The anxiolytic-like activity of PI-ME was assessed by the incidence of rears or steps climbed in the stair case test. The extract at a dose of 200 mg/kg significantly increased the number of climbed steps, although at a higher dose (600 mg/kg) it decreased this parameter. Similarly, the frequency of rears was diminished by the extract at all three doses tested and this outcome was blocked by PTZ. Anxiolytic-like activity has been shown to be associated with an increase in the number of steps climbed by mice whilst sedative activity is thought to be linked to a decrease in the frequency of rears  and this is the very reason why this paradigm was chosen in this species to evaluate P. incarnarta. Other studies have attributed an increased rearing incidence to an anxiety-like behavior and a decreased number of steps climbed to a sedative effect . In conjunction with this, anxiolytic activity has been coupled with lower doses while sedative effects have been related to higher doses of plant extracts or reference drugs . In this context, PI-ME displayed an anxiolytic-like effect at 200 mg/kg, while at 600 mg/kg it exhibited sedative activity. This was also confirmed in the open field test where it was observed that PI-ME decreased the number of lines crossed at doses of 400 and 600 mg/kg comparable to that of diazepam and these findings concur with the literature [17–19, 70]. Since PTZ reversed the anxiolytic-like and sedative actions of PI-ME, underlying GABA mediated mechanisms may well be implicated. In a selection of studies, the sedative and anxiolytic properties of P. incarnata have been attributed to benzodiazepine and GABA receptor mediated biochemical processes in the body [18, 19, 71, 72], binding to GABAA/B sites and inhibition of GABA uptake being of particular consequence .
The modulatory effect of P. incarnata on GABAergic and opioid systems may provide some insight into its beneficial effect in various painful neuropathic conditions. Neuropathy induced hypersensitivity is known to involve disruption of tonic GABAergic transmission  and GABA agonists and metabolic inhibitors have been shown to be effective in various neuropathic nociceptive models [74–76]. Neuropathic pain has been reported to be refractory to opioids [77, 78]. However, several studies have shown that neuropathic pain can be attenuated by morphine and other μ-opioid receptor agonists [79–81] and these reports suggest that local μ-opioid receptors on the terminals of uninjured primary afferent nociceptive neurons are an essential target for alleviating mechanical allodynia. In the current study we have evaluated the methanolic extract of P. incarnata in a novel streptozotocin induced diabetic animal model of neuropathic pain established exclusively in rats . The results showed that PI-ME (200 and 300 mg/kg) induced mechanical anti-allodynic activity exemplified by an increase in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) 1 and 2 h post treatment. Similarly, PI-ME also relieved dynamic vulvodynia by increasing the flinching response latency (FRL) although the extract was devoid of activity on the static component of vulvodynia. The intensity of the PI-ME dynamic anti-vulvodynia response was comparable to that of gabapentin which was used as a reference drug due to the fact that it has proven pain relieving effects in various neuropathic pain models . Gabapentin also exhibits an established propensity to alleviate both static and dynamic components of allodynia and vulvodynia  and the current study corroborates this assertion. The present findings also indicate that the behavioural and antinociceptive effects of PI-ME involve GABAergic and opioidergic mechanisms because they were reversed by PTZ and naloxone respectively. Consequently, it might be inferred that analogous processes are implicated in PI-ME anti-allodynic/vulvodynic activity and this requires a direct focus of further study. In relation to this notion, Ingale and Kasture  suggested that opioidergic as well as the nicotinic cholinergic system are involved in the central analgesic activity of butanolic P. incarnata extract in the eye wipe test. This paradigm is used to study trigeminal pain because corneal nociceptive receptors have a large representation in the trigeminal ganglion through the ophthalmic branch of the trigeminal nerve . Moreover, it has been suggested from radioligand binding studies that it is very unlikely that P. incarnata acts via the benzodiazepine-site of the GABAA-receptor . In this connection, it has been postulated that GABAA α1-sparing benzodiazepine-site ligands might constitute a class of analgesics suitable for the treatment of chronic pain syndromes . Furthermore, there is considerable evidence implicating an important role for diminished GABAergic tone in the development of central sensitization and hyperalgesia in neuropathic pain models [84–86].
The phytochemical screening results of our study verify the presence of a preponderance of flavonoids as well as alkaloids in P. incarnata as described elsewhere [25, 87, 88]. Flavonoids are reported to be the major phytoconstituents of P. incarnata and include chrysin, vitexin, isovitexin, orientin, isoorientin, apigenin and kampferol [14, 30, 89]. These polyphenolic metabolites may play a role in the neuropharmacological activity of several plants [90–92] including P. incarnata [18, 93, 94]. Additionally, flavonoids have been reported to elicit an analgesic effect through opioid  as well as GABAergic systems  and have a beneficial role in relieving neuropathic pain conditions [97–99]. Some flavonoids like quercetin have also been identified in P. incarnata extract  and are believed to be effective in diabetes mellitus induced peripheral neuropathy [101, 102] the activity being mediated through an opioidergic mechanism . The GCMS analysis in this study revealed that P. incarnata contains a predominance of the fatty acid amide 9-octadecenamide (also known as oleamide), which has hypnotic, analgesic, and anxiolytic actions . Many of oleamide’s behavioural effects stem from its activity on various receptor systems including GABAA [105–107], 5HT1A, 5HT2A, 5HT2C, 5HT7 [108–110], G-proteins , voltage gated sodium channels [107, 112] and CB1 receptors . In this respect, oleamide enhances GABA receptor activity and specifically potentiates the peak chloride current when applied with GABA to benzodiazepine-sensitive GABAA receptors . The cannabimimetic action of oleamide resulting from its agonist action at CB1 receptors [110, 113] gives rise to cannabinoid antagonist reversible antinociception which is also sensitive to blockade by the GABAA antagonist bicuculline . It has been posited that endogenous fatty acid derivatives such as oleamide interact with endocannabinoids like anandamide in the modulation of pain sensitivity  which may well contribute to the inhibitory effect of P. incarnata on allodynia and vulvodynia observed in this study.
Other important constituents present in P. incarnata include hexadecanoic acid (palmitic acid), 3-hydroxy-dodecanoic acid, 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-Pyran-4-one, and vitamin-E, that have strong antioxidant and neuroprotective activities and/or modulate the GABAergic system [115–119].
The modulation of GABAergic and/or opioidergic systems by P. incarnata reported in this study may constitute a proportion of the mechanisms implicated in the amelioration of diabetic neuropathy. Additional processes however, like a cannabimimetic action [110, 113, 114] cannot be ignored inasmuch as P. incarnata exhibits antihyperglycemic and hypolipidemic activities in streptozotocin induced diabetes mellitus  which would otherwise lead to neuropathic allodynia and vulvodynia . Hyperglycemia and dyslipidaemia driven oxidative stress is a major contributor to reduced nerve function [120, 121] and diabetes mellitus is a major cause of peripheral neuropathy, commonly manifested as distal symmetrical polyneuropathy . Furthermore, diabetes mellitus has been reported to be linked with vulvodynia either as an isolated symptom or as part of a constellation of other neuropathic abnormalities. Such neuropathic morbidity has been termed ‘diabetic vulvopathy’ and it profoundly affects patient’s quality of life and management needs in order to address the physical, psychological and relationship problems caused by the pain . Our study showed that the methanolic extract of P. incarnata significantly alleviated only the dynamic component of vulvodynia which has been reported more likely to be provoked by contact with clothing among other triggers  and the cotton swab test is usually used to localize painful areas in vulvodynia .
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