Vol. 280, Issue 5, G897-G903, May 2001
Gastroprotective and vasodilatory effects of epidermal growth
factor: the role of sensory afferent neurons
Yoji
Matsumoto1,
Kohki
Kanamoto1,
Keishi
Kawakubo1,
Hitoshi
Aomi1,
Takayuki
Matsumoto2,
Setsuro
Ibayashi1, and
Masatoshi
Fujishima1
1 Department of Medicine and Clinical Science, Graduate
School of Medical Sciences, Kyushu University and
2 Department of Endoscopic Diagnostics and Therapeutics,
Kyushu University Hospital, Fukuoka 812-8582, Japan
 |
ABSTRACT |
Epidermal growth factor
(EGF) has been shown to exert gastric hyperemic and gastroprotective
effects via capsaicin-sensitive afferent neurons, including the release
of calcitonin gene-related peptide (CGRP). We examined the protective
and vasodilatory effects of EGF on the gastric mucosa and its
interaction with sensory nerves, CGRP, and nitric oxide (NO) in
anesthetized rats. Intragastric EGF (10 or 30 µg) significantly
reduced gastric mucosal lesions induced by intragastric 60% ethanol
(50.6% by 10 µg EGF and 70.0% by 30 µg EGF). The protective
effect of EGF was significantly inhibited by pretreatment with
capsaicin desensitization, human CGRP1 antagonist
hCGRP-(8-37), or
N
-nitro-L-arginine methyl ester
(L-NAME). Intravital microscopy showed that topically
applied EGF (10-1,000 µg/ml) dilated the gastric mucosal
arterioles dose dependently and that this vasodilatory effect was
significantly inhibited by equivalent pretreatments. These findings
suggest that EGF plays a protective role against ethanol-induced
gastric mucosal injury, possibly by dilating the gastric mucosal
arterioles via capsaicin-sensitive afferent neurons involving CGRP and
NO mechanisms.
vasodilatation; sensory nerves; calcitonin gene-related peptide; nitric oxide
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INTRODUCTION |
EPIDERMAL GROWTH
FACTOR (EGF) is a polypeptide of 53 amino acids originally
isolated from the rodent submaxillary gland (6). EGF is
continuously secreted from the salivary glands and the duodenal
Brunner's glands (20, 22). Intragastric EGF has been shown to enhance the healing of gastric mucosal injury (20, 22,
30) and to protect the gastric mucosa against various stimuli
such as stress, ethanol, hypertonic saline, and aspirin (12, 16,
21, 24, 26). Recently, much attention has been paid to the
mechanisms by which EGF protects the gastric mucosa; a trophic effect
(7), inhibition of gastric acid secretion (25), enhanced mucus production (18), and the
increase of the gastric mucosal blood flow have been suggested to be
the possible mechanisms (12, 16).
Recent studies have shown that capsaicin-sensitive afferent neurons, as
well as prostaglandins, play an important role in the gastric mucosal
defensive mechanisms in rats. The stimulation of these neurons by
intragastric capsaicin alters the gastric mucosal blood flow (27,
28), motility (33), and acid and HCO
secretion (27, 32) and thus reduces
gastric mucosal damage (11, 17, 38, 41). EGF increases gastric mucosal blood flow and induces gastric mucosal protection, possibly via capsaicin-sensitive afferent neurons (16).
However, the precise mechanisms of the gastric hyperemic and protective effects of EGF are still not fully understood. The aims of the present
experiments were to elucidate 1) whether intragastric EGF
protects the gastric mucosa against ethanol injury, 2)
whether topically applied EGF dilates the gastric mucosal microvessels, and, if so, 3) what are the mechanisms involved.
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MATERIALS AND METHODS |
Animal preparation.
The experiments were reviewed by the Committee on the Ethics of Animal
Experiments at the Graduate School of Medical Sciences, Kyushu
University and were done according to the Guidelines for Animal
Experiments of the Graduate School of Medical Sciences, Kyushu
University and the law (no. 105) and notification (no. 6) of the
Japanese Government.
Male Wistar rats (conventional, 250 g) were fasted for 24 h.
Free access to tap water was allowed before experiments. After anesthetization with intraperitoneal urethane (1.25 g/kg), the rectal
temperature was continuously monitored and maintained between 37 and
38°C with a heating lamp. Systemic blood pressure was monitored via a
catheter inserted in the left femoral artery. To avoid dehydration, saline was continuously infused at a rate of 1.5 ml/h via a catheter inserted in the left femoral vein.
Experiment I.
The possible protective effect of intragastric EGF on the gastric
mucosa of urethane-anesthetized rats was examined. EGF was dissolved in
0.01 M PBS at the appropriate doses. Gastric mucosal injury was induced
by the intragastric application of 60% ethanol (5 ml/kg) through a
plastic cannula intubated orally. Sixty minutes after anesthesia, 10 or
30 µg of EGF in 1 ml PBS or vehicle were orally intubated
(n = 5/group). Fifteen minutes later, the ethanol was
applied topically. The stomach was removed 60 min thereafter and fixed
in 0.5% formalin for 30 min. Then the stomach was cut along the
greater curvature and photographed. The percentage of injured corpus
mucosa was calculated by computerized image analysis (NIH Image, v.
1.61).
The effect of pretreatment with sensory desensitization by capsaicin,
human calcitonin gene-related peptide (CGRP)1 antagonist hCGRP-(8-37), or nitric oxide (NO) synthase inhibitor
N-nitro-L-arginine methyl ester
(L-NAME) was investigated in animals treated with 30 µg
EGF or vehicle (n = 5/group). Capsaicin-sensitive afferent neurons were desensitized through the systemic and functional ablation by capsaicin. As previously described (42),
capsaicin was injected subcutaneously in three consecutive doses of 25, 50, and 50 mg/kg (total of 125 mg/kg) during the 2-wk period before the
experiment. Sensory desensitization was confirmed by instilling a drop
of capsaicin solution (0.1 mg/kg) into an eye of each rat. The instant
response with wiping movements toward the eyes was regarded as
inadequate desensitization. The capsaicin-pretreated rats with a
negative wiping movement test were regarded as functionally ablated and
used for the experiment. Either hCGRP-(8-37) (100 nmol/kg) or L-NAME (10 mg/kg) was bolus injected
intravenously 10 min before the intragastric administration of EGF or
vehicle. L-NAME was given either alone or in combination
with L-arginine (300 mg/kg iv) as a substrate for NO synthase.
Intravital microscopy.
Intravital microscopy was applied by the method reported by Ohono et
al. (29), with a slight modification. Briefly, the stomach
was exposed through a ventral midline abdominal incision and cut along
the greater curvature. After the anterior wall was recected with an
electric cautery scalpel (B-3396; Summit Medical, Tokyo, Japan), the
posterior wall of the glandular stomach was fixed in a plastic chamber
with the mucosal surface facing the bottom and superfused with modified
Krebs buffer (3) (in g/l: 8.0 NaCl, 0.20 KCl, 0.265 CaCl2 · 2H2O, and 2.25 Tris; pH
adjusted to 7.40 with HCl) warmed at 37°C. A small window (3 mm
diameter) was made by a partial removal of the serosa, the smooth
muscle, and the submucosa using microsurgical scissors. Minimal
bleeding during the procedure was controlled with bipolar coagulator
(MICRO-3E; Mizuho Ikakogyo, Tokyo, Japan). Microvasculature in the
basal part of the gastric mucosa was observed through the window by transillumination under a stereomicroscope with a long working-distance objective lens (BX50-33; Olympus, Tokyo, Japan). The images were displayed on a video monitor (PVM-20550M; Sony, Tokyo, Japan) via a
charge-coupled device (CCD) camera (DXC-108; Sony) connected to the microscope.
Experiment II.
The peripheral effect of EGF on gastric mucosal microcirculation was
investigated in urethan-anesthetized rats. The diameter of gastric
mucosal microvessels was measured using the intravital microscopic
technique. After surgery, a resting period of at least 15 min was
allowed to achieve stability of the preparation. Arterioles with inner
diameters of 25-50 µm and 30- to 60-µm venules in the basal
part of the gastric mucosa were examined. A series of increasing concentrations of EGF (0, 10, 20, 40, 100, and 1,000 µg/ml) was topically applied on the gastric wall (20 µl) through the window every 9 min (n = 6/group). Changes in the diameter of
the arteriole and the venule were recorded on videotape for 3 min. The
videotape was played back, and then the maximal diameter of the vessel
was directly measured on the video monitor. The superfusion of the buffer was stopped 15 s before the topical application of EGF and
then was resumed for 6 min until the next application to wash out the
preceding compound.
The effect of pretreatment with sensory desensitization by capsaicin,
hCGRP-(8-37), or L-NAME was tested
(n = 6/group). For sensory desensitization, capsaicin
at 5 mM was superfused for 10 min after the confirmation of arteriolar
dilatation by topical capsaicin at a concentration of 160 µM and then
by modified Krebs solution for 60 min. The arteriolar dilatation
reached a maximum within 1 min after initiation and then remained at
that level for at least 10 min. The arteriolar diameter gradually
returned to the basal value within 60 min after the removal of
capsaicin. In a preliminary experiment, capsaicin desensitization was
confirmed by the second topical capsaicin application 70 min later at a concentration of 160 µM, which has been demonstrated to induce a
maximal response (40). Arteriolar dilatation by the second application of capsaicin was <10%, and therefore the
capsaicin-sensitive afferent neurons were considered to be
desensitized. Either hCGRP-(8-37) (100 nmol/kg)
or L-NAME (10 mg/kg) was bolus injected intravenously 10 min before the topical EGF application (100 µg/ml).
L-NAME was given either alone or in combination with
L-arginine (300 mg/kg iv).
Chemicals and treatments.
The following chemicals were used: EGF (kindly provided by Dr. B. Nakajima, Hitachi Chemical, Japan), capsaicin (Wako Chemical, Osaka,
Japan), hCGRP-(8-37), L-NAME,
L-arginine (Sigma, St. Louis, MO), and ethanol (Wako
Chemical, Osaka, Japan). EGF was dissolved in 0.01 M PBS (Sigma) in
experiment I and in modified Krebs buffer in
experiment II. Capsaicin was dissolved in a solvent composed of 10% ethanol, 10% Tween 80 (Sigma), and 80% vol/vol normal saline (0.15 N NaCl). hCGRP-(8-37), L-NAME, and
L-arginine were dissolved in saline containing 0.1% BSA.
Ethanol was diluted in distilled water. All chemicals were freshly
prepared just before the experiments.
Statistics.
Values are expressed as means ± SE. Student's t-test
was used for comparisons of two groups. Significance of differences was determined with a one-way ANOVA followed by Fischer's protected least
significant difference (PLSD) for the comparison of multiple groups. A
two-factor repeated-measures ANOVA followed by Fisher's PLSD was used
for the data of serial measurements. P values <0.05 were
considered statistically significant.
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RESULTS |
Experiment I.
Gastric mucosal lesions 60 min after ethanol injection occupied
24.3 ± 2.6% of the glandular area in vehicle-treated rats. The
intragastric application of EGF (10 or 30 µg) significantly reduced
the gastric mucosal lesions (12.0 ± 3.5% in the 10 µg group,
P < 0.01, and 7.3 ± 1.3% in the 30 µg group,
P < 0.001, Fig. 1).
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Fig. 1.
The effect of intragastric epidermal growth factor (EGF)
on macroscopic gastric mucosal damage induced by 60% ethanol
(n = 5/ group). Lesion index (%erosions in glandular
stomach) was significantly lower in the groups treated by EGF.
*P < 0.05 and **P < 0.001 vs.
vehicle-treated group. Error bars represent SE.
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Pretreatment with either capsaicin desensitization,
hCGRP-(8-37), or L-NAME slightly, but not
significantly, increased the gastric mucosal lesions (33.9 ± 5.1%, 31.1 ± 6.7%, and 38.2 ± 6.6%, respectively) in the
vehicle-treated rats. All of these pretreatments inhibited the
protective effect of intragastric EGF (30 µg) against ethanol-induced
mucosal lesion [38.6 ± 3.9% in the capsaicin desensitization
group, 33.0 ± 3.7% in the hCGRP-(8-37) group,
and 36.9 ± 5.1% in the L-NAME group,
n = 5, Fig. 2]. There was no significant difference in the gastric mucosal lesions between the vehicle-treated and EGF-treated rats with these pretreatments. Concomitant treatment with L-arginine restored the
protective effect of intragastric EGF in the rats pretreated with
L-NAME (13.3 ± 2.7%, P < 0.001 vs.
L-NAME group, Fig. 2).
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Fig. 2.
The effect of capsaicin desensitization, human calcitonin
gene-related peptide 1 antagonist hCGRP-(8-37), or
N-nitro-L-arginine methyl ester
(L-NAME) on the protective effect of intragastric EGF (30 µg, n = 5/group). Capsaicin desensitization or
pretreatment with hCGRP-(8-37) (100 nmol/kg iv) or
L-NAME (10 mg/kg iv) significantly inhibited the protective
effect of EGF. Concomitant treatment with L-arginine
(L-Arg; 300 mg/kg iv) restored the inhibition induced by
L-NAME. *P < 0.001 vs.
L-NAME-pretreated group. Error bars represent SE.
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Intragastric ethanol increased the mean arterial blood pressure (MABP)
rapidly and significantly by 25-30 mmHg, and MABP returned to the
baseline within 15 min after ethanol injection (data not shown).
Intragastric EGF did not affect of MABP throughout the experiments
(data not shown) compared with the vehicle treatment.
Experiment II.
The basal diameters of the arterioles and venules were 34.5 ± 2.5 µm and 42.5 ± 2.4 µm, respectively. When EGF was applied topically, the arterioles were rapidly dilated, but the venules remained unchanged (Fig. 3A).
Dilatation of the arterioles reached a maximum at 60 s after the
application of the peptides and then remained at a maximum level for
~20 s. The topical application of the vehicle showed little
dilatation of the arterioles (5.4 ± 2.2% , Fig. 3B).
As shown in Fig. 3B, topically applied EGF (10, 20, 40, 100, and 1,000 µg/ml, 20 µl) dilated the arterioles dose dependently
(10.4 ± 1.5%, 13.7 ± 2.0%, 19.4 ± 2.4%, 24.4 ± 3.1%, and 33.7 ± 3.6%, respectively).
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Fig. 3.
A: photographs showing the microvascular changes 60 s after the topical application of EGF (1,000 µg/ml) into the window
on the gastric wall in urethan-anesthetized rats. The topically
administered EGF induced a dilatation of the arterioles (a) but not of
the venules (v). B: percent changes in the diameter of the
arterioles 60 s after the topical application of EGF
(n = 6/group). Topically applied EGF dilated the
arterioles dose dependently. *P < 0.05 and
**P < 0.001 vs. vehicle-treated group. Error bars
represent SE.
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Capsaicin desensitization significantly inhibited the arteriolar
dilatation induced by topically administered capsaicin (160 µM) from
87.5 ± 10.1% to 8.3 ± 1.3% (P < 0.001, Fig. 4). The arteriolar dilatation
induced by topically applied EGF (100 µg/ml) was significantly inhibited by capsaicin desensitization (25.2 ± 1.6% vs. 6.7 ± 1.4%, P < 0.001, Fig.
5).
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Fig. 4.
Comparison of the dilatation of the gastric mucosal
arterioles induced by topical capsaicin (160 µM, n = 6/group). Capsaicin desensitization significantly inhibited the
dilatation of arterioles. *P < 0.001. Error bars
represent SE.
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Fig. 5.
Comparison of the dilatation of the gastric mucosal arterioles
induced by topical EGF (100 µg/ml, n = 6/group).
Capsaicin desensitization, hCGRP-(8-37) (100 nmol/kg
iv), or L-NAME (10 mg/kg iv) significantly inhibited the
dilatation of arterioles. Concomitant treatment with
L-arginine (300 mg/kg iv) restored the inhibition induced
by L-NAME. *P < 0.05 and
**P < 0.001. Error bars represent SE.
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Pretreatment with hCGRP-(8-37) or L-NAME
significantly inhibited the vasodilatory effect of topically
administered EGF (100 µg/ml) from 26.8 ± 6.0% to 5.1 ± 1.6% (P < 0.05) and from 27.4 ± 3.4% to
8.8 ± 2.3% (P < 0.001), respectively (Fig. 5).
Concomitant treatment with L-arginine restored the
L-NAME-induced inhibition of the vasodilatory effect of
topically administered EGF to 20.9 ± 1.9% (P < 0.05 vs. L-NAME group) (Fig. 5).
| |
DISCUSSION |
Our results showed that in urethan-anesthetized rats 1)
intragastric EGF prevents ethanol-induced gastric mucosal injury and topically applied EGF dilates the arterioles but not the venules in the
basal part of gastric mucosa dose dependently and 2) these effects of EGF are mediated through the capsaicin-sensitive afferent neurons via CGRP- and NO-dependent mechanisms. Because EGF was applied
to the serosal side of the glandular stomach in the second experiment,
the effect of EGF on the arteriole observed in the experiment may be
slightly different from that under physiological conditions. However,
our observations suggest that EGF does dilate arterioles in damaged
gastric mucosa that lacks an epithelial layer (i.e., gastric ulcer and erosion).
The EGF receptor (EGF-R) has been shown to belong to the type 1 tyrosine kinase receptor family and to be located in the gastric tissue
of both rodents and humans (31, 34). At the acute and healing stage of gastric mucosal damage, EGF-R has been shown to be
overexpressed in the epithelia (19, 35). It has also been
confirmed in rats that the main source of EGF in the gastric contents
is the submandibular glands (20, 22), and that growth factor exists at a concentration of 19.6 µg/l in the rat
(14). Furthermore, EGF in the salivary glands
(9) and in the gastric juice (23) increases
by severalfold that of the basal value under conditions of gastric
mucosal damage induced by various stimuli. Whereas we applied EGF to
rats at extremely high concentrations compared with those in
physiological conditions, a similar preventive effect of large amounts
of EGF against mucosal injury has been shown in other experiments
(12, 16).
Intragastric EGF protects the gastric mucosa against various stimuli
such as stress, ethanol, hypertonic saline, and aspirin (12, 16,
21, 24, 26). Although parenteral EGF has been shown to decrease
gastric acid secretion (25), intragastric EGF revealed a
protective effect against aspirin- and stress-induced mucosal damage
without reducing acid secretion (24). It thus seems likely
that acid suppression alone is not the significant mechanism of the
protective effect of EGF in our experiments. The trophic action to the
gastric mucosa characterized by increase in DNA, RNA, protein, and
mucus secretion (15, 18) has been confirmed, but this
effect seems to be unrelated to the preventive effect of intragastric
EGF. Cytoprotection through the stimulation of prostaglandin
production by EGF (5, 8) has been suggested to be another
mechanism for the preventive effect. However, the role of prostaglandin
synthesis in the protective effect of EGF still remains controversial
because intragastric EGF exhibited a preventive effect even against
aspirin-induced mucosal injury of the rat stomach without affecting
prostaglandin production (26).
It has been shown in several experiments that intragastric EGF
increases the mucosal blood flow of the stomach. Hui et al. (12) demonstrated that intragastric EGF increased the
blood flow of the rat gastric mucosa after topical ethanol treatment, and it also dose-dependently reduced the degree of mucosal damage. Although Hui et al. (12) measured the mucosal blood flow
by laser-Doppler flowmetry, we directly observed the arterioles in the
gastric mucosa induced by intragastric EGF by using intravital microscopy. Whereas an increase in the gastric mucosal blood flow has
been shown in rats treated by subcutaneous EGF (16), the vasodilatory action of EGF seems to be attributed to an extremely topical response, because the arterioles dilated even after the removal
of submucosal tissue in our experiment.
Recently, the interaction of EGF and NO in the gastric protection has
been investigated in animal experiments (1, 36, 37). Tripp
and Tepperman (37) reported in sialoadenectomized rats
that subcutaneous EGF did not influence NO synthase activity in
ethanol-treated gastric lesions, whereas EGF reduced ethanol-induced mucosal lesions. However, Brzozowski et al. (1) reported
that in stress-induced mucosal lesions an increase in the mucosal blood flow induced by subcutaneous EGF was inhibited by either capsaicin desensitization or NO synthase inhibitor. Our results also indicated a
close interaction between EGF and NO in unsialoadenectomized rats. The
discrepancy in the role of NO in EGF-treated animals may relate to
sialoadenectomy or differences in the route of EGF administration. On
the basis of these previous data and our results, it seems obvious that
EGF induces hyperemia through a NO-dependent mechanism, although the
protective effect of EGF may not be explained by an increase of gastric
mucosal blood flow alone.
It has been established in both rodents and humans that capsaicin plays
a protective role against gastric mucosal injury and that the
capsaicin-sensitive afferent neurons play a major role in the
regulation of the gastric mucosal blood flow (10, 27, 28).
The release of CGRP from stimulated capsaicin-sensitive neurons and
subsequent increase in endothelial NO have been shown to result in
vasodilatation and increase in blood flow (4, 10, 13, 40).
Our results strongly suggested that EGF, as well as capsaicin, dilated
the arteriole through capsaicin-sensitive afferent neurons. Kang et al.
(16) have also reported that the EGF-induced increase in
the blood flow of the rat gastric mucosa was inhibited by either
capsaicin desensitization or hCGRP-(8-37). These
findings suggest that the protective effect of EGF against gastric
mucosal injury is due partly to mucosal hyperemia through the
stimulation of capsaicin-sensitive afferent neurons.
The precise mechanism of stimulation of capsaicin-sensitive neurons by
EGF remains unclear. On the sensory afferent neuron, a receptor, which
is sensitive to capsaicin, protons, and noxious heat, has
recently been cloned and referred to as vanilloid receptor subtype 1 (2). EGF may directly stimulate the vanilloid receptor subtype 1. The stimulation of a capsaicin-sensitive afferent neuron through mast cells may be another explanation, because substances released from these cells have been shown to stimulate the sensory neurons in the rat gastric mucosa (39). However, the EGF
receptors on mast cells remain to be determined.
In past experiments, capsaicin desensitization for sensory neurons was
completed by systemic administration of high dose capsaicin (42), as in our first experiment. The procedure of
desensitization seems to induce a systemic functional depletion of
capsaicin-sensitive neurons. In experiment II, however, we
intentionally applied a high dose of capsaicin directly on the gastric
wall, and a substantial desensitization could thus be achieved. The
method of desensitization coupled with intravital microscopy may be a
model for investigating the role of capsaicin-sensitive afferent
neurons in the regulation of mucosal blood flow.
In conclusion, intragastric EGF plays a protective role against gastric
mucosal injury induced by ethanol, and the effect may be attributable
to hyperemia through stimulation of capsaicin-sensitive afferent
neurons and subsequent CGRP- and NO-dependent mechanisms. It is
presumed that the dilatation of the arterioles may thus be an essential
event in the protective effect of EGF against gastric mucosal injury.
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FOOTNOTES |
Address for reprint requests and other correspondence: Y. Matsumoto, Dept. of Medicine and Clinical Science, Graduate School of
Medical Sciences, Kyushu Univ., Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan (E-mail:
yoji{at}intmed2.med.kyushu-u.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 21 August 2000; accepted in final form 28 November 2000.
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Am J Physiol Gastrointest Liver Physiol 280(5):G897-G903
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