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Involvement of nitric oxide (NO) signalling pathway in the antidepressant activity of essential oil of Valeriana Wallichii patchouli alcohol chemotype.

ABSTRACT

Valeriana wallichii DC (Valerianaceae), popularly named as Indian valerian has been shown to exist as three chemotypes. The present study evaluated the antidepressant like effect of root essential oil of Valeriana wallichii patchouli alcohol chemotype in both acute and chronic treatment study using forced swim test (FST). Mice (n = 6 per group) received 10, 20 and 40mg/kg p.o. doses of test drug. Single administration of oil significantly inhibited the immobility period (57.6% and 46.9%) at doses 20 and 40mg/kg respectively without changing the motor function (p<0.05). Similarly, daily administration of essential oil (20 mg/kg) for 14 days significantly reduced the immobility period (69.9%) in FST (p < 0.05). The neurotransmitter levels in mouse brain were estimated on day 14 after the behavioral study. Significant increase in the level of norepinephrine (29%) and serotonin (19%) (p < 0.05) was found at 20 mg/kg dose, while no change was observed at 10 and 40 mg/kg doses. The antidepressant-like effect of essential oil (20 mg/kg) was prevented by pretreatment of mice with L-arginine (750 mg/kg i.p.) and sildenafil (5 mg/kg i.p). On the contrary, pretreatment of mice with l-NAME (10 mg/kg i.p.) or methylene blue (10 mg/kg i.p.) potentiated the antidepressant action of essential oil (10 mg/kg). Taken together, these findings demonstrated that nitric oxide pathway is involved in mediating antidepressant like effect of essential oil from this chemotype.

[c] 2011 Elsevier GmbH. All rights reserved.

ARTICLE INFO

Keywords:

Valeriana wallichii DC chemotype

Essential oil

Forced swim test

Nitric oxide modulators

Neurotransmitters

Introduction

Depression, the major public health problem, is provoked by exposure to chronic stress (Sakakibara et al. 2008). The abnormalities of noradrenergic, dopaminergic and serotonergic transmission are known to cause mental depression (Berton and Nestler 2006). During the past few years, nitric oxide (NO), an inorganic free radical has emerged as an important signal and effector molecule in several biological processes including vasodilatation, inflammation and neurotransmission (Lowenstein et al. 1994). The data accumulated in the last two decades indicate that NO, a messenger molecule regulates neurotransmission in the central nervous system. It has been implicated in synaptic plasticity, learning, perception of pain, aggression, depression and is an ideal mediator of nonsynaptic interactions (Esplugues 2002). Monoaminergic systems participate mainly in nonsynaptic interactions hence, NO may have an important role in the regulation of monoaminergic systems. Reduction of NO levels within the brain can induce antidepressant-like effects and therefore, L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) is an important signalling pathway that is reported to be involved in depression (Harkin et al. 1999; Mantovani et al. 2003). Various studies have shown the possibility that the inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants (Harkin et al. 1999).

The roots of Valeriana wallichii D.C (Indian Valerian), a counter part of European Valeriana officinalis L, is used as stimulant, diuretic, carminative and antispasmodic (Strachey 1918). It is also used for the treatment of epilepsy, hysteria, chorea, shell shock, neurosis, ulcers, asthma, jaundice and has traditionally been used as constituent in hypnotic herbal drugs (Sharma 2003). V. wallichii has been claimed to possess effect on central nervous system in various preclinical studies (Cao and Hong 1994). The roots are used in Indian systems of medicine but it is only recently established that Valeriana wallichii exists as three chemically distinct chemotypes characterized by patchouli alcohol, maaliol and kanokonyl acetate respectively (Mathela et al. 2005a, b, 2009).

The antidepressant-like effect of herbal formulations with V. wallichii as one of the ingredient has been reported (Shalam et al. 2007). Another study reports antidepressant activity of aqueous, methanolic and aqueous-ethanolic extract of V. wallichii in forced swim test and tail suspension test (Subhan et al. 2009). The roots and rhizomes of V. wallichii contain essential oil contributing to its bioactivity. Thus, the aim of the present study was to evaluate the effect of essential oil of Valeriana wallichii chemotype patchouli alcohol, a principal chemotype, on forced swim test and to explore the mechanism responsible for this effect.

Materials and methods

Plant material

Roots and rhizomes of V. wallichii were collected from Kumaun region of India during October and the plant was authenticated from Botanical Survey of India, Dehradun (Voucher specimen number Chem/DST/V.II).

Extraction of essential oil

The fresh plant material was subjected to steam distillation in a copper still fitted with spiral glass condensers. The distillate was saturated with NaCl and the oil was extracted with n-hexane and dichloromethane. The organic phase was evaporated under reduced pressure in a thin film rotatory evaporator at 30 [degrees] C. The yield of the oil was 0.60% (v/w) and was coded as EOVW.

GC and GC-MS analysis of essential oil

The GC analysis of essential oil was performed on a Nucon 5765 gas chromatograph (Rtx-5 column, 30 m x 0.32 mm i.d., FID, split ratio 1: 48, [N.sub.2] flow of 4kg/[cm.sub,2]) and on a Thermo Quest Trace GC 2000 interfaced with a Finnigan MAT Polaris Q ion-trap mass spectrometer fitted with an Rtx-5 fused silica capillary column (30 m x 0.25 [mu] m i.d.; 0.25 [mu] m film coating; Restek Corp.). The column temperature was programmed from 60 to 210 [degrees] C at 3 [degrees]/min; carrier gas, helium (1.0 [mu] /min); injector temperature 210 [degrees] C; injection vol., 0.1 ml in hexane; split ratio, 1:40. MS were recorded at 70 eV with a mass scan range of 40-450 amu. Mass spectra were taken at 70 ev (EI) with mass scan range of m\z 40-450amu with mass scan time of 4s. A co-injection was made of mixture of oil and n-alkanes ([C.sup.8]-[C.sup.21]) to determine the retention indices. Identification of the constituents was done on the basis of retention indices (Kovats 1965) and their mass spectra (NIST& WILEY), which were compared with literature data (Adams 2001). Column chromatography (on silica gel, 250-400 mesh) separated some major constituents which were identified by IR, MS, and NMR data.

Animals

Albino Laca mice (20-30g, age 10 months) bred in the Central Animal House facility of Punjab University, Chandigarh, India were used for the study. The animals had free access to standard rodent food pellets and water. They were acclimatized to the laboratory conditions before the experiment and all the experiments were conducted between 09.00 and 17.00 h. The experimental protocol was approved by the Institutional Animal Ethics Committee, Punjab University, Chandigarh and conducted according to the National Science Academy Guidelines for the use and care of animals.

Drugs and treatment

Imipramine, sildenafil (Sigma Aldrich Co., USA), L-arginine (Hi-Media, Mumbai), methylene blue (HiMedia, Mumbai), l-NAME (N-omega-nitro-1-arginine-methyl-ester) a nitric oxide synthase inhibitor. Essential oil (EOVW) of V. wallichii chemotype Patchouli alcohol. Imipramine, L-arginine, methylene blue, l-NAME, sildenafil were dissolved in distilled water and test drug was dissolved in 2% (v/v)Tween80.

Experimental protocol

Acute toxicity studies

Acute toxicity test was performed according to the Organization for Economic Cooperation Development (OECD) Guidelines no. 423 (OECD Guidelines 1996). It was based on a stepwise procedure with the use of a minimum number of animals per step. Three female nulliparous and non pregnant albino laca mice were used for each step (each dose level). The dose level to be used as the starting dose was selected from one of three fixed dose levels of 25, 200 and 2000 mg/kg. b. W (OECD Guidelines 1996). The animals were fasted before the oral administration of the extract and observed individually, after dosing, at least once during the first 30 rnin, periodically during the first 24 h, with special attention given during the first 4 h and daily thereafter, for a total of 14 days. The animals were observed for general behavior and any toxic symptoms produced by the oil, such as cyanosis, tremors, convulsions, ataxia, extension of the limbs, increased muscle tone, piloerection, tail flick, salivation, drowsiness, diarrhea, ptosis, respiratory effects, arched back, loss of righting, abdominal gripping and blanching. The number of animals that die in a 14 days period after a single dose was recorded.

Locomotor activity

The locomotor activity was monitored using actophotometer (IMCORP, India). The animals were individually placed in activity meter for 3 min before counting of actual locomotor activity for the next 5 min. The locomotor activity was expressed in terms of total photobeams counts, 5 min per animal (Reddy et al. 1998).

Forced swim test

In the acute treatment study, EOVW (10, 20 and 40 mg/kg, p.o. dissolved in 2%(v/v)Tween 80 solution)and imipramine( 10 mg/kg, p.o.) were administered 1 h before the forced swim test. In the chronic treatment study, the same dosages of EOVW or imipramine were administered once a day for 2 weeks and the final treatment was conducted 1 h before the behavioral test. Negative control animals were treated with 2% (v/v) Tween 80 solution. In this test mice were individually forced to swim inside a rectangular glass jar (25cm x 12cm x 25cm containing 15cm of water maintained at 23-25 [degrees] C). The total immobility time for the period of 6 min was recorded with the help of a stop-watch (Kulkarni and Mehta 1985).

Measurement of biogenic amines

The neurotransmitter levels (serotonin, dopamine and norepinephrine) were estimated by high performance liquid chromatography (HPLC) with electrochemical detector (ECD) (Beyer et al. 2002). Soon after the measurement of immobility period in FST on day 14, animals were sacrificed, brains were removed and stored at -80 [degrees] C Brain samples were homogenized in homogenizing solution containing 0.1 M perchloric acid and 1 x [10.sup.-7] M ascorbic acid. After that, samples were centrifuged at 24,000 x g for 15 min. The supernatant was further filtered through 0.25 [mu] m nylon filters before injecting in the HPLC injection pump. All the samples were run between 15 and 20 min of preparation and were stored in ice prior to analysis. [Waters.sup.[R]] standard system consisting of a high pressure isocratic pump, a 20 [mu] 1 sample injector valve, C18 reverse phase column and electrochemical detector were used. Mobile phase consisted of 0.15 M Na[H.sub.2]P[O.sub.4], 0,25 mM EDTA, 1.75 mM 1-octane sulfonic acid, 2% isopropanol and 4% methanol (pH 4.8). Electrochemical conditions for the experiment were +0.800 V, sensitivity ranges from 1 to 100 nA. Separation was carried out at a flow rate of 1 ml/min. Samples (20 [mu] 1) were injected manually. Norepinephrine, dopamine (Sigma) and serotonin (ICN, Biochemical Inc.) were used as standards. The working standard solutions were prepared in 0.1 M perchloric acid containing 0.1 mM ascorbic acid and stored at 4 [degrees]C. Peaks were identified by comparing the retention time of each peak in the sample solution to that of individual peak in the standard solution, and by superimposing the chromatograms of the samples spiked with and without known amounts of the standard solutions. The retention time was 2.5 min, 4.8 min and 8.5 min for norepinephrine, dopamine and serotonin respectively. The calibration curves of norepinephrine, dopamine and serotonin were drawn with standard concentrations ranging from 10 to 100 [mu]g/ml. The regression equations were calculated in the form ofy = ax + b, where y and x correspond to the peak area and concentration, respectively. Using this equation, the relative quantity of neurotransmitters in the brain samples was determined. The pmoles of norepinephrine, dopamine and serotonin were calculated and the final data was reported as percentage. Data were recorded and analysed with the help of [Empower.sup.[R]] software provided by [Waters.sup.[R]] (Beyer et al. 2002).

Effect of nitric oxide modulators on the antidepressant-like activity of essential oil

For studying the possible participation of the L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant like effect of essential oil in FST, mice were pretreated with L-arginine, a precursor of nitric oxide (750 mg/kg, i.p., a dose that produces no effect in the forced swim test), or vehicle (Dhir and Kulkarni 2007). Five minutes after L-arginine, EOVW (20 mg/kg, p.o., a dose active in the FST and having no effect on the locomotor activity) or vehicle was injected and 60 min later animals were subjected to FST. In another set of experiments, effect of EOVW (10 mg/kg, p.o., a subeffective dose) with l-NAME (5 mg/kg, i.p., an inhibitor of nitric oxide synthase) or methylene blue (10 mg/kg, i.p., an inhibitor of nitric oxide synthase and an inhibitor of soluble guanylate cyclase) was investigated. These modulators were administered 5 min before EOVW or vehicle and 60 min later challenged with FST. To observe the role of cGMP in the antidepressant action of EOVW, mice received an injection of sildenafil (5 mg/kg, i.p., phosphodiesterase 5 inhibitor) or vehicle 5 min before EOVW (20 mg/kg, i.p.). Sixty minutes after EOVW administration the animals were subjected to FST.

Statistical analysis

The results were expressed as mean [+ or -] SEM. The intergroup variation was measured by one-way analysis of variance (ANOVA) followed by Tukey's test. Statistical significance was considered at p<0.05. The statistical analysis was done using the Jandel Sigma Stat statistical Software.

Results

GC and GC-MS analysis of essential oil

The gas chromatogram of the essential oil showed the presence of nearly 28 peaks of which 20 have been identified and comprised approximately 97% of the oil, dominated by sesquiterpenoids followed by monoterpenes. The oil contains patchouli alcohol (40.2%) as the major constituent followed by the presence of 8-guaiene (10.7%), seychellene (8.2%), 8-acetoxyl patchouli alcohol (4.5%) and virdiflorol (5.2%) (Table 1).
Table 1 The constituents present in the essential
oil of V. wallichii (patchouli alcohol chemotype).

Compound                      % content  Method of characterization

a-Pinene                      1.5        a, b
Camphene                      1.8        a, b
(3-Pinene                     2.9        a. b
Methyl thymol                 1.3        a, b
Methyl carvacrol              2.5        a, b
Bornyl acetate                1.9        a, b, c
S-Guaiene                     10.7       a, b, c
(3-CaryophylIene              1.6        a, b
(3-Gurjunene                  0.5        a, b
a-Guaiene                     4.3        a, b
Y-Patchoulene                 1.2        a, b
a-Patchoulene                 4.3        a, b
Seychellene                   8.2        a, b
Valencene                     1.1        a, b
a-Muurolene                   1.7        a, b
Kessane                       1.2        a, b
Viridiflorol                  5.2        a, b, c
Guaiol                        0.8        a, b
Patchouli alcohol             40.2       a, b, c
8-Acetoxyl patchouli alcohol  4.5        a, b, c

a = Linear Retention Index(LRI)onRtx-5non polar capillary
column, b-MS (GC-MS), c = [H.sub.1] & [C.sup.13], NMR.
Constituents above 4% are shown by bold faces.


Acute toxicity studies

The dose level to be used as the starting dose was 200 mg/kg. No mortality was found at this dose level so additional three mice were tested at 200 mg/kg. As there was no mortality, the dose was increased to next level i.e. 2000 mg/kg b.w. and the procedure was repeated as above. The animals did not show any toxic and abnormal symptoms up to the single oral dose of 2000 mg/kg and no mortality (L[D.sub.0]) was found up to this particular dose.

Effect on locomotor activity

No significant decrease in locomotor activity was observed at the tested doses of EOVW (Table 2). Imipramine, the standard drug, was also devoid of any effect on locomotor activity.
Table 2 Effect of single administration of essential oil
(EOVW) in actophotometer apparatus in mice

Treatment       Mean ambulatory scores

Vehicle         414 [+ or -]13.6
EOVW(10)        383 [+ or -]45.4
EOVW (20)       415 [+ or -]62.9
EOVW (40)          319[+ or -]36
Imipramine(l0)    300 [+ or -]40

EOVW = essential oil.


Effect of acute administration of EOVW in forced swim test

Dose dependent decrease in immobility was observed after single oral administration of different doses of EOVW, and the effect was significant at 40 mg/kg (57.6% decrease) and 20 mg/kg (46.9% decrease) (p<0.05) (Fig. 1). Group treated with standard drug imipramine produced 36.2% decrease in immobility (p<0.05).

Effect of chronic administration of EOVW in forced swim test

In chronic study, EOVW was effective in reducing immobility period at 20 mg/kg dose while no effect was seen at 10 and 40 mg/kg doses, thus it produced a U shaped curve. The reduction in immobility was 69.9% at 20 mg/kg dose (p<0.05) (Fig. 2).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Effect of chronic administration ofEOVW on the neurotransmitter levels in mouse brain

When checked for alterations in the neurotransmitter levels after 14 days of dosing of EOVW, significant increase in the level of norepinephrine (19%) and serotonin (29%) was observed at 20 mg/kg, while there was no significant change in the level of dopamine (11%) (p< 0.05). EOVW was ineffective in increasing the level of norepinephrine, dopamine and serotonin at 10 mg/kg (data not shown) and 40 mg/kg doses (Fig. 3). Imipramine at 10 mg/kg displayed no significant change in the norepinephrine (18%) and dopamine (12%) levels but there was a significant increase in the level of serotonin (40%) in the whole brain (p<0.05) (Fig. 3).

Effect of nitric oxide modulators on antidepressant-like effect of EOVW

Pretreatment with subeffective dose of L-arginine (750 mg/kg i.p., nitric oxide precursor) reversed the antidepressant action of EOVW (20 mg/kg) as shown by increase in immobility period compared to EOVW (20mg/kg) perse group (Fig. 4). L-NAME (10mg/kg i.p.), enhanced the antidepressant effect of EOVW (10 mg/kg) (Fig. 5) (p<0.05). L-NAME per se did not have any effect on immobility period in FST.

Methylene blue (10 mg/kg i.p.) did not affect the immobility time perse however, it significantly enhanced the antidepressant effect of lower dose of EOVW (10 mg/kg) (p<0.05) (Fig. 6).

Sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor) did not affect immobility perse, but pretreatment with sildenafil reversed the antidepressant effect ofEOVW (20 mg/kg) (Fig. 7).

Combination studies ofEOVW with all the nitric oxide modulators did not affect the locomotor activity of mice as compared to effect perse (data not shown).

Discussion

The present study demonstrated the antidepressant effect of essential oil of Valeriana wallichii patchouli alcohol chemotype, in the forced swim test, in mice. There are few studies reporting antidepressant activity of V. wallichii (Shalam et al. 2007) but no study has been done so far elucidating its possible mechanism of action. Methanol extract of Japanese valerian (Valeriana fauriei) also exhibited strong antidepressant activity in the forced swimming test in mice. The active fraction was identified as a sesquiterpenoid called as kessyl alcohol and its activity compared favorably to that of imipramine (Oshimaand Matsuoka 1995).

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

[FIGURE 7 OMITTED]

In the present study single administration of essential oil produced a dose dependent effect and the effect was significant at 20 and 40mg/kg doses. Further, chronic administration of essential oil EOVW produced a U shaped curve and the effect was found to be significant at 20mg/kg in comparison to vehicle control. Psychostimulants, which exert an indiscriminate motor stimulating activity, have previously been shown to be efficacious in decreasing immobility in FST, but devoid of antidepressant activity. In order to exclude a false positive result, we employed an additional test to check motor stimulating activity of oil and no alteration in locomotor activity was seen with EOVW at any doses. Furthermore, the chronic administration of EOVW for 14 days differentially modulated the biogenic amines levels. Lower dose (20 mg/kg) of essential oil significantly increased the levels of norepinephrine and serotonin while higher dose (40 mg/kg) did not increase the level of any of the neurotransmitter significantly. The results obtained correlate well with the results obtained in forced swim test. Therefore the reduction in immobility period by essential oil could be attributed to an inherent antidepressant like effect.

Many experimental and clinical data support that the extracts of Hypericum perforatum popularly known as St. John's Wort, exhibit antidepressant actions (Rodriguez-Landa and Contreras 2003; Knuppel and Linde 2004). A study depicts 57% reduction in immobility with 500mg/kg dose of the total extract of Hypericum perforatum after single administration (Butterweck et al. 1997) while in our study, 40 mg/kg dose of essential oil of V. wallichii (patchouli alcohol chemotype) produced 57.6% decrease after single administration. The present study suggests that the oil is more potent in producing antidepressant action as compared to extracts of other plants with antidepressant action like Salvia elegans, YuejuWan, Hypericum perforatum (Butterweck et al. 1997; Herrera-Ruiz et al. 2006; Wei et al. 2008).

This study also investigated the involvement of the L-arginine-NO-cGMP pathway in the antidepressant-like effect of V. wallichii essential oil. In many studies nitric oxide synthase inhibitors have been reported to possess antidepressant-like effect at doses that are without any effect on locomotor activity (Harkin et al. 1999). In this study, the pretreatment of mice with the NOS substrate, L-arginine, or with sildenafil (a phosphodiesterase 5 inhibitor) resulted in the reversal of the antidepressant action of EOVW as shown by the increase in immobility period as compared to EOVW perse group. On the contrary to this, NO synthase inhibitor L-NAME and methylene blue augmented the behavioral effect of EOVW in the forced swim test. These results indicate that the effect of essential oil in the forced swimming test may be dependent on the inhibition of NO synthesis. Our results are in accordance with previous studies that have shown that the reduction of NO levels within the brain can induce antidepressant-like effects (Brocardo et al. 2008; Cristiano et al. 2008; Francesco 2010). Thus nitric oxide plays a significant neuromodulatory role in the CNS and pharmacological manipulation of NO pathway may be considered as a novel therapeutic approach for the management of CNS disorders, like mental depression (Heiberg et al. 2002). The antidepressant drugs like paroxetine and venlafaxine were also found to have antidepressant effect via nitregic system blocking effect in mouse FST (Dhir and Kulkarni 2007; Ghasemi et al. 2009).

There are several studies reporting inhibition of NO in lipopolysaccharide (LPS)-activated RAW 264.7 cells by terpenes, and sesquiterpenoids have been found to have suppressive effect on nitric oxide synthase activity (Posadas et al. 2001; Lee et al. 2002; Yoon et al. 2008). Moreover, a study reports nitric oxide inhibiting properties of many terpenes (Bourgou et al. 2010). GC-MS analysis of essential oil EOVW suggested that it contains over 20 constituents dominated by sesquiterpenoids, patchouli alcohol being chemotypic marker compound followed by 8-guaiene, seychellene, 8-acetoxyl patchouli alcohol and virdiflorol. It is thus possible that terpenes present in oil might be responsible for the antidepressant action by modulation of nitric oxide signalling pathway.

The U-shaped activity curve observed in this study may be due to multiple receptor action and has also been reported for some herbal medicines (Sakakibara et al. 2008). Other reason may be due to, both facilitatory and inhibitory effect of NO on the NMDA receptor, as it regulates NMDA receptor activity in a biphasic manner playing both a positive and negative modulatory role (Manzoni and Bockaert 1993). In addition, such mechanisms may help explain why so many contradictory results have been found suggesting that NO either facilitates or inhibits NMDA receptor mediated events such as seizures, nociception, neurotoxicity, anxiolysis and depression (Harkin et al. 1999).

All these results suggest that the nitric oxide inhibition elicited by the constituents of essential oil EOVW leads to a critical NO concentration which in turn, alters the vesicular release of neurotransmitters, like norepinephrine and serotonin involved in depression.

Acknowledgements

The grant from Department of Science and Technology, Government of India, New Delhi for conducting the study is gratefully acknowledged.

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Sangeeta Pilkhwal Sah (a), (*) Chandra Shekhar Mathela (b), Kanwaljit Chopra (c)

(a) Department of Pharmaceutical Sciences, Kumaun University, Nainital, Uttarakhand 263136, India

(b) Department of Chemistry, Kumaun University, Nainital, Uttarakhand 263001, India

(c) University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

* Corresponding author. Tel.: 91 5942 248307.

E-mail address: spilkhwal@yahoo.com (S.P. Sah).

doi: 10.1016/j.phymed.2011.06.009
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Author:Sah, Sangeeta Pilkhwa; Mathela, Chandra Shekhar; Chopra, Kanwaljit
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Nov 15, 2011
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