14: 141-160, 1984
OF TSH - INDEPENDENT THYROID GROWTH
Andrzej Lewinski, Susan Webb and Russel J. Reiter. Department of Experimental Endocrinology, Institute of Endocrinology, Medical Academy of bddi, 91-425 hodi, Dr. Sterling str. 3, Poland (A.L.); Department of Endocrinology, San Pablo Hospital, Autonomous University of Barcelona, AV. San Antonio M. Claret Spain (S.W.), and 167, Barcelona-15, Department of Anatomy, The University of- Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284, USA (R.J.R.) ABSTRACT -____ Considerable evidence has been accumulated which indicates the participation of the autonomic nervous system in the growth of adrenals, ovaries, testes thyroid and lobes. Results have been gathered indicating that the pituitary is not required for the growth of the thyroid, adrenals and ovaries; interest is currently focused on the involvement of the pineal gland in the control of growth not only of the gonads, but also of the thyroid. This paper summarizes the data currently available on the concepts of thyroid hypertrophic and hyperplastic mechanisms, which occur independently of thyrotropin (.TSH), and which suggest the existence of a reciprocal relationship between the pineal and the thyroid. INTRODUCTION Since a direct innervation of the adrenal gland (1) and of the ovary (2) was discovered, a remarkable number of studies have been aimed at determining the role of the nervous system in compensatory hypertrophy and hyperplasia after unilateral removal of peripheral endocrine glands (3, 4). The existence of a pure neuronal mechanism in the development of compensatory hypertrophy of the adrenal gland (5) and of the ovary (6) has been proposed. A body of evidence against corticotropin (ACTH) as the sole mediator of compensatory adrenal growth has accumulated (7-14). Accordingly, the corticosterone-ACTH negative feedback has been suggested not to primarily control compensatory adrenal hypertrophy (15). The participation of both the afferent (3, 16-18j and efferent (3, 19) neural elements in adrenal hypertrophic mechanisms, has been proved. On the basis of these data, the involvement of a neural reflex in contralateral adrenal growth after unilateral manipulation, has been suggested (14).
In other studies, unilateral deafferentation of the medio-basal hypothalamus (MBH) inhibited compensatory ovarian hypertrophy following unilateral ovariectomy, only when both interventions were performed deafferentation contralateral to ipsilaterally; a similar the ovariectomy was ineffective (20). Further, a unilateral lesion of the hypothalamic arcuate nucleus, prevented the development of compensatory ovarian hypertrophy when brain surgery was carried out on the same side as the unilateral ovariectomy (21). These data speak in favor of the participation of both afferent and efferent neural pathways in the observed turn, ovariectomy (22) or phenomena. unilateral cellular activity in the orchidectomy (23) higher resuged in hypothalamic arcuate neurons contralateral to the hemigonadectomy. These asymmetric reactions of symmetric structures would again indicate that neural pathways are involved (2.4). Local treatment of the remaining ovary with 6-hydroxydopamine (6-OHDA), a neurotoxin known to destroy catecholaminergic nerve endings, prevented the development of compensatory ovarian hypertrophy after unilateral ovariectomy (4). Both surgical denervation and local 6-UHDA demonstrated to testicular treatment were reduce weight (25). Furthermore, it has been shown that the pituitary is not required for the compensatory growth of the adrenals (7, 11, 13). Consistently, unilateral ovariectomy partially prevented atrophy of the remaining ovary in hypophysectomized rats (26). In the light of the above data, it was of interest to us to in the investigate whether similar mechanisms were also. operative thyroid gland. It should be emphasized that the thyroid gland in the rat and in the mouse can be considered as a paired endocrine gland, since each thyroid lobe has an ipsilateral sympathetic innervation, and the isthmus contains little or no glandular tissue. PARTICIPATION
OF THE SYMPATHETIC NERVOUS SYSTEM IN THYROID GROWTH
Sympathetic innervation of the thyroid has been demonstrated in It derives from the superior cervical many animal species (27). It has been shown ganglia, as does the innervation of the pineal gland. that some terminals of postganglionic, norepinephrine-containing nerves are located very close to the thyroid follicular cells, separated only the follicular basement membrane The existence of a (28). by morphological basis for a direct, nonvascular influence of sympathetic nerves on the thyroid has been postulated (29), and the thyroid follicular cells have been as possible neuroendocrine considered transducer cells (30). It should be emphasized that the thyroid not only possesses an adrenergic, but also a cholinergic innervation (31, 32), as well as non-cholinergic, non-adrenergic nerves showing immunoreactivity for vasoactive intestinal peptide (VIP) (33, 34). The function of the two latter awaits elucidation; however, it was hypothesized that these nerves might be involved, as the adrenergic fibers, in the control of thyroid activity (32, 33).
the view that the influence of the nervous system on the Thus, thyroid is mediated nearly exclusively through the pituitary, should be In accordance with this, we were able to demonstrate the revised. following phenomena: 1) We have investigated the compensatory thyroid hyperplasia (CTH) following direct intrathyroidal injections of- 6-OHDA (35)) a substance In these which specifically destroys catecholaminergic nerve endings. experiments, local treatment of the thyroid lobe with 6-OHDA inhibited suggesting the CTH after contralateral hemithyroidectomy (hemiTXj, involvement of efferent pathways of the neural reflex in the mechanism “pharmacological hemiTX” by a of this Moreover, growth (Fig. 1A). microinjection of the thyroi.d lobe with 6-OHDA brought about CTH of the contralateral thyroid lobe. Since both thyroid lobes would be expected to grow after unilateral manipulation if the signals were humoral, the originated by the destruction of results suggest a neural reflex afferent elements in the injected lobe (Fig. 1A). It shoulti be recalled here that the exact morphological configuration of the affer-ent-efferent pathways carrying the signals from one thyroid lobe to another is, up to now, unknown. 2) We have observed CTH after contralateral hcmiTX i 11 hypophysectomized rats which suggests that the pituitary is not rcquir-rd for the thyroid growth in these animals (36) (Fig. IR). The presumed presence in plasma of hypophysectomized rdts of TSH originating from extrapituitary sources (37)) is hardly probable. Although ,a,I immunoreactive TSH-like peptide has been demonstrated in rats both in the hypothalamus and in extrahypothalamic brain areas, this brain TSH does not appear to serve as a reserve pool of hormone, since it does nnt change at all after thyroidectomy, as do pituitary and plasma TSH (‘?X). 3) Further, we have found CTH in the remaining thyroid lobe at trr hemiTX in Snell dwarf mice (39). Since in Sriell dwarfs not only growth hormone (GH) and prolactin (40)) but also TSH is lacking (41, 42), thc,sr animals are believed to be a good modrl for investigatiorl ot ‘I’SHindependent proliferogenic reactions of the thyroid gland. We suggrs,t ?li that extrapituitary factors, most probably neural pathways, nest tw involved in thyroid follicular cell proliferation in these animals (Fig. 1C). 4) We have also reported that ieft side posterior deaffcreutat ION of the hypothalamus significantly reduces the basal mitotic act ivlty rate of both thyroid lobes and prevents the hemiTX-induced increase 1 11 mitotic activity of the remaining thyroid lobe in rats (43) (Fig. ID). The mechanism responsible for these findings remains unclear, but the assumption can be offered that neural pathways directly participate I IL the control of thyroid growth, for posterior deafferentation ot the hypothalamus has been shown not to affect the secretory TSH profi It-s 1u rats (44). Some observations from other laboratories t h8 t suggest the regulation of thyroid growth in certain conditions can bc ‘I‘SHindependent. The thyroid of hypophysectomized animals grows to s,,me extent in iodine deficiency (45). Thyroid cell diffrrentation oicl~r-s
Schematic drawing demonstrating the TSH-independent thyroid Figure 1. growth or its inhibition. For further explanations see text. MNL Multineuronal link, Af - Afferent part of the hypothetical MNL, Ef Efferent part of the hypothetical MNL, HemiTX - Hemithyroidectomy, HYPOX - Hypophysectomy, L - Left side, R - Right side, LPD - Left posterior deafferentation, Sham-LPD - Sham deafferentation, 6-OHDA 6-Hydroxydopamine, TSH - Thyrotropin.
after TSH elimination, i.e., in decapitated fetuses (46). In many studies on human subjects, no correlation between the rate of goiter It is well enlargement and serum TSH level has been found (47, 48). documented that the direct stimulatory effect of some pituitary tropins (ACTH, TSH) on the growth of the respective endocrine glands is fairly distinct only in vivo (49, 50). On the contrary, in culture, ACTH inhibits the proliferation of the adrenocortical cells (51), while LH blocks the proliferation of the luteal cells (52). Studies dealing with the effect of TSH on thyroid cell proliferation in vitro have produced divergent results (53, 54); it has even been shown that TSH is not a growth factor for human thyroid cells in culture (54). This casts doubt on the mitogenic action of TSH on the thyroid, particularly because in vivo , the desensitization of the rat thyroid to the growth-stimulating action of TSH in hypophysectomized rats (55), as well as in intact rats during prolonged goitrogen administration (56) has been reported. It is worth recalling that not only growth, but also the function of the gland, both in health and disease, can be influenced by the sympathetic nervous system (for review see ref. no. 57). A correlation between increased activity of the sympathetic nervous system and hyperthyroidism was suggested over 100 years ago (58); it seems unquestionable that sympathetic overactivity can precipitate and/or worsen the symptoms of this disease (59). These clinical observations are related to an enhanced thyroid hormone secretion. The sympathetic nervous system is also believed to mediate the rapid adaptations of thyroid hormone secretion to appropriate physiological stimuli (28). INVOLVEMENT OF THE PINEAL AND THE SUPERIOR CERVICAL GANGLIA IN THE CONTROL OF THYROID GROWTH I'he unique relationship between the pineal and the thyroid derives from the fact that both these glands are innervated from a common source, namely, the superior cervical (60). ganglia (SCG) Simultaneously, this anatomical cl-ear relation precludes the interpretation of the results from experiments where the denervation of the thyroid is performed by superior cervical ganglionectomy (SCGX), since this surgical procedure also entails denervation of the pineal gland, which itself affects thyroid function and growth (see below). It has been shown in methylmercaptoimidazole (MMI) - treated rats that SCGX causes greater increase of thyroid weight than that in shamSCGX rats (61). This effect was not related to changes in TSH levels, since plasma TSH responses were almost the same in MMI-treated SCGX, and MMI-treated sham-SCGX rats. The pineal gland did not participate in this phenomenon either, because the thyroid enlargement following MM1 treatment in pinealectomized (PX) rats was indistinguishable from that in sham-PX animals and TSH levels were similar in MMI-treated PX, and in MMI-treated sham-PX rats. In other words, pinealectomy (PX) did not mimic the action of SCGX on thyroid growth, thus the latter should not be considered simply as pineal denervation. In the same report, the progoitrogenic effect of SCGX was suggested even without treatment Yuith MMI, as TSH administration to SCGX-animals caused greater thyroid hypertrophy than in TSH-treated The above cited sham-SCGX controls. results confirm, on the one hand, the participation of the sympathetic
nervous system, but on the other would seem to indicate that these nerves play an inhibitory role in the control of thyroid growth. However, the explanation of this phenomenon is not clearcut, since in other experiments from the same laboratory (62) SCGX was shown to decrease TSH levels significantly in the acute experiment (14 hours after surgery) and this effect could not be observed in PX animals. Summing up the findings after SCGX from both reports would lead us to the obvious conclusion that TSH decrease is unlikely to produce thyroid growth. Other results clearly speak in favor of the influence of adrenergic nerves ( deriving Twelve days from SCG, on thyroid growth. after removal of the right SCG, hypertrophy of the ipsilateral thyroid lobe only was observed (63). It thyroid
can be (either
therefore, that “pharmacological”
denervation of local b-OHDA),
denervation by SCGX, should be the preferable method, since it does entail fulictional changes of other structures, impeding, in this data interpretation. Due to the complexity of the possible way, interrelations between SCG, the thyroid, the pineal gland and its two of hormones (indoles and peptides), as well as due to the fact types that lighting conditions affect pineal activity, the experimental protocols should he designed very carefully, trying to avoid all the pitfalls which can arise. Pineal control of the hypothalamo-pituitary-thyroid axis has recently been a subject of interest for many investigators (64-66). An inhibitory effect of the pineal gland on pituitary TSH secretion has been well documented (67-69). Experimental activation of the pineal gland by reducing the length of the photoperiod or by blinding hamsters has been shown to decrease plasma thyroxine (T4) levels and to reduce plasma free-thyroxine indices (7Oj. Nelatonin administration has also Pinealbeen reported to decrease plasma T4 levels in hamsters (71). induced inhibition of thyrotropin releasing hormone (TRH) liberation into portal vessels has been proposed as an explanation of the the site of antithyroid influence of the pineal gland (72). However, inhibition of axis has not been the hypothalamo-pituitary-thyroid since data supporting a direct peripheral effect determined precisely, of the pineal gland on the thyroid are also available; namely, the removal of the pituitary did not prevent the thyroid weight increase suggests a direct effect of the pineal gland on thyroid after PX, which growth (73). Studies
on the histological appearance and growth of the thyroid, have yielded contradictory results. While many authors have reported an increase in thyroid size and weight after PX (73-78)) others have not (67, 79, 80). Histological changes in the thyroid, suggesting increased activity of the gland, similar to those observed after TSH administration, have also been described after PX (75, 76); however, other investigators have found no substantial histological changes in the thyroid following surgical removal of the pineal and others have shown changes (73)) It has been unlikely to accompany the increased thyroid activity (81j. found that PX increases the mitotic activity of thyroid follicular cells (82) ; unfortunately, no numerical data were available in this study, and
employed in this type c’f no stathmokinetic method, usually It has been previously well established investigation, was reported. dependent on lighting the activity of the pineal gland is that conditions and increases in animals subjected to longer dark-exposure the maintenance of gerbils under short photoperiod (83). Accordingly, results in an increased number of pineal concretions (84), indicating enhanced metabolic activity of the pineal (85). The role of lighting so far, conditions in the control of thyroid growth remains, unclear Results from our studies demonstrated that subjecting (67, 80, 86). adult mice to short photoperiods resulted in a decrease of- mit.oti~c activity rate of thyroid follicular cells, when compared to animals reared under long photoperiod (87). On the basis of these data, the affect yuestion of whether lighting conditions themselves the proliferation of thyroid follicular cells or if the observed phenomenon reflects only the dark-induced pineal activation or light-induced pineal blockade, cannot be adequately answered. However, an assumption may be offered that thyroid growth is under the inhibitory control exerted by the pineal gland, this pineal effect can be blocked by the and maintenance of animals in long photoperiods. Such an interpretation is compatible with the previous reports showing thyroid hypertrophy after PX in rats (73, 75, 76), mice (77)) and cats (74). Furthermore, the present results are in agreement with the earlier study demonstrating attenuation of thiourea-induced enlargement in thyroid hamsters maintained in short photoperiods (86); in the same report the authors demonstrated that the inhibitory effect of longer dark-exposure on thyroid hypertrophy is independent of the presence of the pineal gland. We attempted to clarify the respective effects of lighting conditions and the presence of the pineal itself on thyroid activity by karyometric examination of thyroid follicular cells. We have shown a significantly lower mean nuclear volume (MNV) of follicular cells in gerbils with intact pineals, in comparison to PX animals. Lighting conditions were only effective in the presence of the pineal, namely, short photoperiod-exposure brought about further reduction of MNV, when compared to sham-PX animals maintained in long photoperiods. In the same study, lighting conditions did not affect the MNV of follicular cells in PX gerbils. These data suggest that the pineal gland itself, not light deprivation, is the most important factor depressing the thyroid activity. Lighting conditions appear to influence the function of thyroid follicular cells inasmuch as they activate or block the it is to be stressed that the action of the pineal gland. However, above discussed karyometric study reflects the function of the thyroid rather than the growth; the dependence of the latter on light exposure is not sufficiently clear. The assumption that the pineal gland decreases the proliferation of thyroid follicular cells, an effect which can be revealed by subjecting is supported by the experiments where the animals to short photoperiods, Administration of the pineal hormone melatonin has been employed. melatonin has been reported to inhibit thyroid hypertrophy after methylthiouracil (MTlJ)-treatment (89), or following PX (77, 78), but not to affect the thyroid weight in untreated controls with intact pineals melatonin has been shown to decrease the (78, 89, 90). Furthermore, height of the thyroid follicular cells not only in MTU-treated rats, but
also in untreated controls (89)) which is in compliance with the PX-induced increase of height in question (82). While for some authors administration of pineal extracts to rats was followed by signs of thyroid involution (75, 91), other investigators postulated a In one goitrogenic effect of melatonin on the thyroid (78, 92). hyperactivity were laboratory, histological thyroid signs of surprisingly observed after melatonin treatment (90). the aforementioned Summing up, all of the pineal gland in the control activity of- thyroid follicular cells. the hypothesis presented below.
reports show the relevant role of secretory and proliferative These data lead us to formulate
HYPOTHESIS OF TSH-INDEPENDENTREGULATIONOF THYROID GROWTH .___.During normal function of the hypothalamo-pituitary-thyro id axis, the effect of TSH on thyroid growth appears to be the most important one. The TSH-independent control of thyroid growth becomes apparent in the following circumstances: 1. In experiments, in which the higher levels of the hypothalamopituitary-thyroid axis have been disturbed by a mutilating surgical left-side posterior deafferentation of the intervention (hypophysectomy, such as PX, exogenous hypothalamus), or modulated by factors administration of the pineal indoleamine melatonin, artificial lighting conditions, and SCGX; it is our hypothesis that these latter factors would influence the thyroid directly without affecting the hypothalamus or the pituitary. 2. affected possibly
In experiments, directly (surgical SCGX).
which the thyroid or “pharmacological”
innervation has been thyroid denervation;
Additionally, the thyroid growth can be hypothetically the sympathetic nervous system in the same situations in function is influenced. These include: 3. In natural conditions, environmental changes. 4.
affected by which thyroid
Regarding points 1. and 2.) thyroid growth in the abscence of TSH has been demonstrated in hypophysectomized rats (36) and in Snell dwarf mice with genetically determined TSH absence (39). Furthermore, thyroid cell proliferation is inhibited by left-side posterior deafferentation a procedure which does not affect TSH profiles. These data (43)) suggest that extrapituitary factors, most probably neural, are invol.ved in the thyroid growth. In compliance with this, adrenergic nerve fibers, both afferent and efferent, are believed to participate in thyroid hyperplasia direct mechanisms Moreover, not only (35). “pharmacological hemithyroidectomy” with 6-OHDA, but also SCGX has been shown to influence thyroid growth, independently of the hypothalamopituitary-thyroid axis (61, 63).
environmental psychotrauma onset
changes followed clinically
with experimental sympathetic nervous
points is by overt results system
known to increase a hyperadrenergic
function; can even
The possible interrelations TSH-independent thyroid growth, are
(59); this is in inf lurnce the direct function (28, 93). involved
agreement t.hc 0f
All the aforementioned considerations do not mean that in norjnal animals with intact pituitaries, TSH is devuid of its prolif-erogenic action on the thyroid, and do not negate the participation of TSH in the mechanism of CTH. Moreover, we succeded to prove a substantial role uf TSH in the proliferation of thyroid follicular cells in the remaining thyroid lobe after hemiTX (36, 39, 94, 95). What we wanted to stress here, is that the view that the influence of the nervous systr,m on the peripheral endocrine glands is mediated almost exclusively Ily the, pituitary, should be revised. Much rlvidence has been a~cumulat ed indicating the existence connect ions betwec>n Lhe of direct neural It has been shown hypothalamus and peripheral endocrine glands (5, 24). that the medio-basal to the spinal cord, Further, a functionally occur in rats (97).
hypothalamus and which relevant
(MRH) contains neurons also receive affcrents link between the SCG and
which pr-o,iec t from it (Ot-1). MHH appears to
We do not intend to deny the obvious facts (discussed LII tlrt:ji 1 above), demonstrating that the pineal gland is a modulator r)t t hr hypothalamo-pituitary-thyroid axis, acting mostly at the hypothalamic otpituitary level. What we would like to stress here, is the possibility of TRH-TSH-independent interactions between thr pineal and thyr(oi[l growth, which could occur by an until now unknown neural mechanism connecting both glands (the common source of their inuervation makes this problem even more interesting). h;e do not exclude a rrcilbr-cc ill interrelationship between these two glands, i.e., the thyroid c.o111d hypothetically affect the growth of pinealocytes, the same as the pi I:W;II influences the proliferation of thyrocytes. Another possibility is that pineal influences the thyroid directly, via
between or by axis
the thyroid and the pineal, which cd11 .Ict a humoral transmission of signals (Figure .!). would be an alternative model of thyr-oitl regulation of thyI- i 11 independently oi the basal function and growth through the hypothalamo-pituitary-thyroid axls. 111 this model, lighting conditions could be the moduldtor of the p~nral gland activity, but we do not exclude the direct influence of IIght exposure on TSH secretion, thus on the hypothalamo-pituitdry-thyl-1) id axis. Similarly, SCGX can itself modulate thyroid growth, but it is rlc,t unlikely that it can affect TSH levels independently of the pineal. I)llr hypothesis is supported by the finding that pinealectomy suhstnrlt l;illy attenuates the atrophic changes in the thyroid of hypophysec tomi zccl
I I I I I I I I
I i I
I I I I
I I I
I I I I
I I I
I I I I I I I I I I I I I \
GH EGF Insulin
EVf -/ndependenf Roufe
- - -
TSH - Depended
General model of possible reciprocal relationships between Figure 2. the pineal gland, the superior cervical ganglia and the thyroid, EGF - Epidermal growth involved in the control of thyroid growth. LP - Long photoperiod, SP - Short factor, GH - Growth hormone, photoperiod, MBH - Medio-basal hypothalamus, MEL - Melatonin, MNL Multineuronal link, SCG - Superior cervical ganglion, TGI - Thyroid growth-blocking TGBI - Thyroid growth-stimulating immunoglobulins, immunoglobulins, TSH - Thyrotropin, TRH - Thyrotropin releasing hormone, T3 - Triiodothyronine, T4 - Thyroxine.
rats, which means that the relation between the pineal and the thyroid has been shown to occur in the absence of the pituitary (73, 98). Moreover, it is documented that removal of the pineal gland also determines an increase of the rate of nucleic acid synthesis and the rate of mitosis incidence in other tissues, which are not the target organs for pituitary tropins, such as the spleen and the intestinal mucosa (99). In other studies, reversal by melatonin of the growth promoting effect of PX on transplanted melanoma in hamsters was observed (100). Other factors which affect thyroid growth independently of TSH are the thyroid growth-stimulating immunoglobulins (TGI) (101, 102). These antibodies are believed to promote the growth of the gland rather than its secretion, and are responsible, among others, for the not infrequent clinical occurrence of fast-growing, neutral goiters. Additionally, the thyroid growth-blocking immunoglobulins (TGBI) have been discovered (103). The significance of these immunological phenomena involved in the regulation of thyroid function and growth is beyond the scope of the present paper (for review see ref. no. 104). Not only the sympathetic nervous system and the pineal gland via neural links or direct melatonin action on the thyroid can influence its TSH-independent growth. It is to be recalled that other hormones can also participate in the regulation of thyroid growth. Such an assumed proliferogenic factor for the thyroid could be for instance, insulin (105), epidermal growth factor (EGF) (106), or GH (107). Finally, it is tempting to speculate that not the hypothalamus and the pituitary, but the pineal gland is the highest level of regulation of growth and function of not only the thyroid gland, but also other paired endocrine glands. CONCLUSIONS Summarizing, the following TSH-independent thyroid growth:
Sympathetic innervation of the gland, deriving from the SCG.
The pineal gland through the direct action of melatonin at the thyroid level, or through yet unknown multineuronal links connecting both these glands, without participation of the higher levels of the hypothalamo-pituitary-thyroidaxis. This implies the possible existence of a direct pineal-thyroid feedback system.
Thyroid growth-stimulating immunoglobulins (TGI), as well as thyroid growth-blocking immunoglobulins (TGBI).
Hormones other than TSH, i.e., GH, epidermal growth factor (EGF) and insulin.
the thyroid raises feedback mechanisms peripheral endocrine
a re,ciprocal relationship between the pineal and the possibility that direct, growth-controlling also occur between the pineal and other paired organs. ACKNOWLEDGEMENTS _
The work was supported in part by grants from the Polish Academy of Sciences, no. 10.4.2.01.5.5., from the Ministry of Health and Social Welfare of Poland, no. lo-RMZ-VII-I, and by NSF grant no. PCM 8003441. The authors wish S.W. is a recipient of d Fulbright Commission Grant. Nancy Elms for her excellent secretarial assistance and to thank Mrs. Mr. Robert Jones for his skillful graphical work. REFERENCES _____ 1.
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