Endo-Optimize Supplement

Posted By Braverman IVF & Reproductive Immunology || 6-Jun-2016

A Natural Supplement for our patients with poor egg quality due to Endometriosis

A Supplement Formulated By Dr. Braverman

Recent Literature confirms that many of the problems with egg and embryo quality in patients with endometriosis may be due to mitochondrial dysfunction. We believe through mitochondria optimization we may improve egg and embryo quality in these patients. In fact, over the years, we have seen significant improvement in our patients' egg and embryo quality that have used the combination of supplements that are in our product. While this may be due to other therapies that we may have introduced, we believe the supplements may have played a part in this change. The ingredients in our supplements have substantial support from research in peer review journals for their ability to effect change in mitochondrial function and even inhibit the growth of endometriosis lesions.

Dr. Jeffrey Braverman is a pioneer in the field of Reproductive immunology. His clinical work has focused on the role of the immune system in the development of immune related conditions such as Recurrent Pregnancy Loss, Endometriosis and Infertility.

Dr. Andrea Vidali is a Reproductive Surgeon and Reproductive Endocrinologist who specializes in Endometriosis Treatment.

Surgery is an essential treatment for Endometriosis but it needs to be complemented by medical treatment.

Regardless if you are being treated for endometriosis for pain, infertility or miscarriage, the medical community acknowledges that, although surgery is helpful, there is a high recurrence rate. This is because Endometriosis is an immunologically mediated condition. The source of which is a defect in the endometrial cells that attain 2 new characteristics. First the ability to grow in locations they would normally not be found i.e. into the muscle (adenomyosis) and in the abdominal cavity (endometriosis). Second they now gain the ability to secrete inflammatory proteins called cytokines that appear to be directly responsible for the destruction of follicles causing decreased ovarian reserve and the damage of mitochondria during egg development leading to poor egg/embryo quality.

Natural Treatment of Endometriosis

Figure 1: Overview of the molecular mechanisms
leading to the growth of endometriotic lesions

Despite the fact that much research has been carried out for decades, very limited medical treatments are available for endometriosis and most of them have very undesirable side effects.

We have extensive clinical experience with each ingredient and we have been recommending these ingredients for years.

Over the years we prescribed all of the ingredients contained in our supplement for our patients with endometriosis related infertility. These of course had to be purchased separately and at many times different locations. In our practice we have seen substantial improvement in embryo behavior and pregnancy rates in patients that were on all of these supplements. Centers around the world have copied our supplement protocol. Now we have put all of these supplements into one pill.

ALL IN ONE pill: a more efficient and less unpleasant way of taking all the supplements we recommend for Endometriosis

One of the problems with supplementation is that, in order to get the right ingredients one is forced to ingest dozens of pills per day. This can become very cumbersome. Also studies have shown that the frustration of having to take so many supplements leads patients to interrupt their schedule of taking all the supplements.. This is why Endo Optimize contains all the right ingredients, in the right dosages that we have successfully used in our clinical practice for years.

We have developed a supplement with ingredients that have been shown to address reproductive issues associated with endometriosis. The ingredients in Endo Optimize have also been shown to have pain relieving qualities as well. Please read the countless testimonials from our patients that have had success on this supplement protocol over the last 10 years.

Many commercially available supplements provide a high number of ingredients in minimal dosages. Unfortunately most ingredients in generic supplements are there just for”window dressing”. Through our clinical work we have identified the key ingredients that we have been prescribing to our patients over the years. We produce our supplement in a GMP facility, the supplement has also been analyzed by an independent lab to confirm that the content matches the amount declared on the label. The supplement is also free of undesirable ingredients like magnesium stearate. Also of importance is that our supplements were tested and certified to be completely Gluten Free.

The Right Ingredients in the Right Formulation and the Right Dosage in a Vegetarian Capsule.


Melatonin is by nature an agent able to pass through any cellular membranes. It is a potent anti-oxidant that prevents oxidative stress induced by reactive oxygen species. While melatonin has a direct effect on oxidative stress by scavenging ROS and RNS (1), its metabolites (product of its degradation) are also active and act indirectly by inducing the production of anti-oxidative enzymes and lowering the synthesis of pro-oxidative molecules (2) leading to an overall reduction of oxidative stress.

In the FF, melatonin eliminates free radicals and stimulates antioxidant enzymes in addition to promote sex steroid hormone production by granulosa cells which support follicle development leading to ovulation (3).
Melatonin plays also a key role during the luteal phase protecting the luteal granulosa cells from oxidative damage leading to apoptosis and preventing the occurrence of a premature new menstrual cycle. It maintains progesterone production by the corpus luteum which supports the luteal phase.

There are many clinical studies assessing the use of melatonin during IVF cycles although most of them have been conducted with patients as their own controls and not through a randomized, double blinded comparison between treated patients “melatonin group” and proper controls “placebo group”.

A study (4) assessing the effects of oral administration of melatonin (3mg/day) in patients from day 5 until oocyte collection showed significant increase in fertilization rates as compared to the precedent cycle for the same patients (50% vs 20.2%).

A small randomized study (5) with N=60 patients where melatonin was orally administrated (3mg/day) from day 3-5 until hCG administration (oocyte collection) showed:

  • a higher number of total oocytes (11.5 vs 6.9)
  • higher number of mature oocyte (9% vs 4.4%)
  • a higher rate of embryos transferred (69.3% vs 44.8%)

These results were confirmed in another independent trial (6).

Animal studies showed that melatonin can reduce endometriotic lesions (7) although it has not been assessed in women.

Nevertheless, a recent study has shown promising results in PCOS patients with restoration of menstrual cyclicity (lowering testosterone and AMH levels, increasing FSH with no alteration of glycemic or lipid parameters) when administrated at 2mg/day for 6 months (8).

Melatonin use is safe and did not show any teratogenic effects in both human and animal (9-10) as well as no toxicity (11) even at very high dose (5-20mg/day).
Given the potential clinical benefits of melatonin and its safety, it is a target of choice to counteract oxidative stress and enhance oocyte/embryo quality.


Myo-inositol belongs to the vitamin B complex. It is the precursor for the synthesis of phosphoinosides, which are part of the phosphatidylinositol signal transduction pathway (12). This pathway is responsible of signal transduction across the plasma membrane, via a second messenger, inositol 1,4,5-triphosphate, that modulates intracellular Ca2+ release as seen in Figure 2.

Figure 2: Phosphatidyl inositol pathway leading to calcium release.

Myo-inositol and the ovarian function

Through its effects on the calcium pathway, myo-inositol plays a direct and key role on the maturation of an oocyte (egg) which leads to better oocyte quality and increased ovulation rate (13-15). Further this has an impact on fertilization and early embryo development (16).
Thus, myo-inositol significantly increases fertilization and pregnancy success rate (17) which is suggested by its role during the stages of early development in the embryo (18).

Indeed, a double blinded trial (13) assessed the effects of myo-inositol on the ovarian function by comparing PCOS patients on 2g MYO + 200mcg folic acid (twice a day) for 3 months (treated group) versus PCOS patients on 200mcg folic acid (twice a day) for the same period length (control group).

The oocyte quality was assessed at ovum pick up and showed:

  • rFSH administrated during stimulation was significantly lower in the treated group which significantly decreases the risk of hyperstimulation.
  • Increased number of oocytes retrieved in the treated group (12 versus 8.5)
  • Higher % of mature oocyte in the treated group (82% versus 63%)
  • % of immature oocyte (degenerated or vesicle germinal) was significantly reduced in the treated group (2.3% versus 24%)
  • Higher % of score 1 embryos (good quality embryo) in the treated group (70% vs. 30%).

The treatment with myo-inositol in addition to melatonin improves ovarian stimulation protocols and pregnancy outcomes in infertile women with poor oocyte quality (17).
It is important to also highlight that levels of myo-inositol in the follicular fluid are good marker of oocyte quality in animal study (19) but also in women during IVF procedure (20). Further, myo-inositol is also able to significantly lower leptin levels that are markers for poor oocyte quality (21).

Myoinositol and PCOS

Another important aspect of inositols is their role as insulin-sensitizers that could have several benefits in PCOS patients.
Besides their powerful antioxidant potential (22) that reduces oxidative stress, myo-inositol can also help decrease hyperandrogenism (lowering testosterone levels) and sensitize the ovary to insulin (23).

Further, a study assessing hormonal parameters in obese PCOS patients before and after 12 weeks of treatment (24) with myo-inositol at 2g/day in addition to folic acid (200mg) and comparing the changes to control individuals (treated with folic acid 200mg only) showed exclusively in patients treated with myo-inositol:

  • A significant reduction in insulin levels
  • A significant reduction in prolactin levels
  • A significant reduction in LH levels

In addition, myo-inositol had a clear impact on treated patients’ fertility who had much higher % of top-quality oocytes (82% vs. 36%) resulting in 40% of clinical pregnancies (vs 16% for the control group).

Myo-inositol supplementation is efficient in positively modulating many of the hormonal disturbances of PCOS, and overall leading to better ovarian function.

It could be used as an agent to help restore better oocyte quality leading tobetter embryo quality and higher chances of getting pregnant.

Pine Tree Bark: Pycnogenol

Pycnogenol® (PYC) is a plant extract obtained from the bark of the French maritime pine Pinus pinaster. It has strong antioxidant activity and is used as a phytochemical remedy for various diseases.
In Vitro study in human lymphocytes showed its potent anti-oxidant potential as well as its abilities to reduce DNA damage and chromosome breakage induced by chemicals (25).
Pycnogenol has been shown to exert anti-inflammatory and antithrombotic effects (26) by inhibiting Cox-1 and Cox-2 enzymatic activity (27), both involved in the inflammatory pathway.
PYC is also able to significantly reduce pain associated with endometriosis, which is even reduced when combined with oral contraceptives after 3-months use (28). These effects are mediated through the suppression of NF-KB-dependent gene expression, which activates the inflammatory cascade (29).
In a study including N=58 patients affected by endometriosis and surgically diagnosed with the condition, the use of pycnogenol at 60mg/day for 48 weeks significantly reduced the symptoms score (N=26) as well as CA-125 levels (a serum marker of endometriosis) although in patients treated with hormones therapy (N=26), the benefits are even more pronounced.

Coq10: (Ubiquinol)

A natural fertility enhancer

The maturation of an oocyte leading to ovulation is a complex process requiring the formation of the meiotic spindle and the production of energy by mitochondria (30).
A disrupted mitochondrial function could lead to arrest of oocyte maturation, chromosomal misalignment, and could compromise embryo development (31-33).
CoQ10 is an essential component of the electron transport chain involved in energy (ATP) production (34), further it has critical anti-oxidant properties (35).

A murine model for ovarian aging showed that mitochondria are not fully functional in aged ovaries as seen by decreased metabolic activities (36). As a result, aged animals produced oocytes with spindle defects leading to misaligned chromosomes (that will induce impaired cell division).
Interestingly, most of these abnormalities could be partially or completely corrected by the administration of CoQ10 in animal models.
Besides changes in the mitochondria, it has been shown that older animals have lower number of granulosa cells (GC, cells surrounding the oocyte and supporting the growth of the oocyte) and these cells express lower CoQ10 expression levels.
CoQ10 treatment significantly increases GC numbers in these aged mice (36).
In the same study, the genetic deletion in the oocyte of a specific enzyme Pdss2 (leading to its inactivation), involved in the CoQ10 synthesis led to aged oocytes in young mice with:

  • Premature ovarian failure
  • Reduction of follicle number
  • Poor ovulation response to stimulation
  • Decreased ATP production and mitochondrial activity in the few aged oocytes.

Altogether, these data suggest that a lack of CoQ10 could be responsible for a premature aging of the ovarian function with detrimental effects on oocyte quality.
Most interestingly, CoQ10 supplementation could be used to counteract and even reverse the effects of aging on follicle development.

Indeed, a clinical trial has been led in women and showed interesting results.
In the randomized, double-blind-study including IVF-ICSI patients between 35-43 years old, women were treated with either 600mg CoQ10 (N=17) or equivalent dose of placebo (N=22) for 2 months prior and during their IVF cycle (37).
The rate of oocyte aneuploidy (using polar body biopsies) was 46.5% in the CoQ10 group compared to 62.8% in the controls. Clinical pregnancy rate was 33% for the CoQ10 group and 26.7% for the control group. Although, the difference was not significant due to the limited number of patients enrolled in the study, the data showed a trend towards oocyte improvement in CoQ10 treated patients.

In addition, levels of CoQ10 in the follicular fluid of N=20 infertile women correlate with oocyte maturation and embryo grade during in vitro fertilization (38).
Another study (39) on N=60 patients undergoing ICSI showed that higher follicular fluid CoQ10 level were associated with grade A-B embryos (0.53 µg/mL) as compared to grade C-D embryos (0.39 µg/mL).
Further, embryos leading to pregnancy were obtained from oocyte with higher follicular CoQ10 levels (0.6 µg/mL) when compared to those leading to failed implantation (0.38 µg/mL).
Other studies have shown that low plasma CoQ10 levels correlates with subsequent spontaneous abortions (40).

CoQ10 and PCOS

Besides its beneficial effects on fertility, CoQ10 could also improve glucose metabolism and lipid profile in PCOS patients (41). A randomize, double-blind, placebo controlled trial where patients were administrated with 100mg CoQ10 daily (N=30) or placebo (N=30) for 12 weeks showed that treated patients have:

  • Significantly lower fasting plasma glucose
  • Significantly lower serum insulin concentration
  • Significantly lower total cholesterol concentration
  • Significantly lower LDL-cholesterol concentration

So Overall, CoQ10 supplementation for 12 weeks among subjects with PCOS had beneficial effects on glucose metabolism, serum total- and LDL-cholesterol levels.

In PCOS patients (42) resistant to clomiphene citrate induction, CoQ10 could induce ovulation when combined to clomiphene citrate (N=51, 65.9% ovulation/cycle) as compared to controls (N=50 patients treated with clomiphene citrate alone, 15.5% ovulation/cycle) which leads to higher pregnancy rate per patient (37.3% vs 6%).

Lastly, CoQ10 reduces gamma glutamyltransferase, a specific enzyme involves in oxidative stress within 14 days of 150mg/day CoQ10 administration.

Altogether, these results are supportive of the usage of CoQ10 as a supplement in women fertility.


Resveratrol is a polyphenolic compound isolated from the skin of red grapes and berries and found in red wine. In addition to its anti-inflammatory properties, it is a natural aromatase inhibitor (43), an enzyme involved in the synthesis of estradiol and has also antiproliferative and anti-oxidant properties (44).

Resveratrol and the ovarian function

In the ovary, resveratrol can activate a specific receptor and increases its expression, namely SIRT1 (45), present in oocyte and granulosa cells at different stages of the follicular development. The sirtuin pathway plays a key role in promoting mitochondrial biogenesis (46). This pathway is also involved in:

  • sensoring the oxidative stress levels in oocyte and granulosa cells
  • activating the steroidogenesis associated with luteinization (progesterone production)
  • repressing the pro-inflammatory NF-KB pathway
  • repressing the synthesis of COX enzyme involved in prostaglandins production (pro-inflammatory pathway)

A recent mice study (47) showed that resveratrol promotes ovary and oocyte quality by interfering with a pesticide (mancozeb) used to induce accumulations of ROS (marker of oxidative stress). As a result, the abnormal mitochondrial function, the increased follicle apoptosis, the decreased development of mature oocyte is significantly minimized using resveratrol thus improving the reproductive outcomes. Similar effects were also reported in porcine oocytes cultured with resveratrol where mitochondrial functions including ATP generation were improved as well as the developmental ability of the oocytes to the blastocyst stages (48).
In addition, resveratrol increased the ovarian follicular reserve and prolonged the ovarian life span in rats (49) by increasing AMH levels and reducing ovarian inflammation through SIRT1 regulation among other mechanisms, leading to the inhibition of the pro-inflammatory NF-KB pathway.

Resveratrol and endometriosis

A recent and elegant study revealed that infertility related to endometriosis may be due to oocyte (egg) DNA damages induced by oxidative stress (50). Most importantly, the study further suggested that oxidative stress (the main cause of oocyte DNA damage) could be reversed using anti-oxidants such as resveratrol and melatonin thus rescuing the oocyte and leading to its development and maturation to give rise to a fertilizable egg.

To assess the effects of oxidative stress on oocyte development, the authors of the study exposed in vitro, immature healthy mouse oocyte to follicular fluid from women affected by endometriosis (ENDO-FF). They monitored the oocyte development and compared it to immature mouse oocyte cultured with follicular fluid from healthy women (controls patients not affected by endometriosis).
Results showed that Endo-FF induced:
- Higher levels of ROS in the mouse oocyte
- Higher levels of DNA damage in the mouse oocyte
- Decrease or a delay in oocyte maturation as compared to controls

Oocyte maturation was impaired by Endo-FF and the oocytes’ development was blocked.
Interestingly, the oocyte maturation was blocked at a very specific development stage (metaphase I arrest) where a sensor for DNA damage (Spindle Assembly Check point/Dna Damage Response) assesses the DNA integrity and blocks the oocyte maturation through the activation of a protein (ATM kinase).
The study showed that ROS directly activates this blocking protein to stop oocyte development.
Further, the authors showed that oocyte maturation could be rescued by inhibiting or lowering ROS levels using resveratrol and melatonin in the culture medium.
It is very important to note that the noxious effects of ROS and pro-inflammatory factors presents in the follicular fluid of ENDO patients (such as IL-6, TNF-α) would be even more accentuated in human ovary where oocytes are exposed to follicular fluid at higher concentrations and for longer periods of time than in the current study.

In a mice model for endometriosis (51), endometriotic human implants were injected in the peritoneal cavity. Mice were treated by estradiol alone daily for 12 days (controls) or in combination with resveratrol daily for 20 days (controls). Mice were sacrificed and endometriotic lesions were assessed.
Results showed a 60% reduction in the number of lesions and an 80% reduction in the lesions’ volume in mice treated with resveratrol as compared to the control group (estradiol only). In the same study, in vitro investigations showed that resveratrol significantly reduce the invasiveness potential of human endometrial cells by up to 78%.
Besides confirming these results, another study run in rats (52-53) showed a significant decrease in pro-angiogenic factors such as VEGF at both serum and peritoneal fluid levels, but also a significant decrease in pro-inflammatory molecules such as MCP-1 in the peritoneal fluid and at the serum level. In addition, resveratrol-treated rats showed endometriotic lesions improvement (decreased number and volume) with significant decrease in oxidative stress (54) as shown by reduced activities of superoxide dismutase and glutathione peroxidase (two enzymes involved in the generation of oxidative stress).

Based on animal and In Vitro studies (55), resveratrol appears to be effective in counteracting the development of endometriosis through its antiangiogenic, anti-inflammatory properties, inhibiting the adhesion and proliferation of endometriotic lesions and reducing the oxidative stress.

Resveratrol and PCOS

The therapeutic potential of resveratrol in the treatment of PCOS has been postulated because this polyphenol promotes apoptosis (56) and reduces androgen synthesis (57) in ovarian theca cells.

A mice model for PCOS has been developed (ob/ob mice that are also leptin deficient), where mice are:

- obese

- hyperglycemic

- hyperinsulinemic

- insulin-resistant

- exhibiting increased TNF-a and IL-6 levels, which promotes the state of chronic low-grade inflammation.

A study (58) assessing the effects of resveratrol on metabolic parameters in ob/ob mice injected daily with resveratrol for 20 days or left untreated (as controls) showed that resveratrol:

  • reduces testosterone
  • reduces insulin levels
  • reduced TNF-α and IL-6 levels in adipose tissue

In a rat model for PCOS (59), daily intraperitoneal injection of resveratrol for 4 weeks induced:

  • a significant reduction in the number of antral follicle counts
  • a significantly decreased plasma anti-Mullerian hormone and insulin-like growth factor 1 levels (playing a key role in PCOS metabolic disturbances)
  • significantly lower superoxide dismutase activity
  • significantly increased glutathione peroxidase which will reduce cell vulnerability to ROS.

Altogether these data showed that resveratrol is effective in the treatment of PCOS through its antioxidant properties.


Curcumin (diferuloylmethane) is the golden spice in Indian saffron and the most active constituent of turmeric. It has been consumed by people for centuries to treat a variety of proinflammatory ailments.
It has been shown to have high anti-oxidant potential (60). It also has anti-inflammatory properties and has been shown as a valuable agent to prevent inflammatory damage in a model of intestinal disease (61) or in a model of chronic kidney disease (62).

Studies led in animal models showed a positive impact of curcumin on ovarian function.
A mice model of immune ovarian failure (63) where, a factor NF-kappa B leading to pro-inflammatory factors secretion, triggers the follicular cell death, curcumin has been shown to:

  • attenuate the inflammatory response.
  • promote the proliferation of granulosa cells by reducing the apoptosis process leading to cell death
  • support the oocyte maturation that was impaired in this mice model
  • promote the synthesis of sex steroid hormones

Other in-vivo studies have demonstrated the benefits of curcumin in supporting follicle development and steroidogenesis (64-66).

Curcumin has shown some promising results with potential therapeutic use in the prevention and treatment of endometriosis. An in vitro study (67), where human ectopic endometriotic cells were cultured with curcumin, showed a significant inhibition of TNF-α-induced secretion of IL-6, IL-8 and MCP-1, known actors in the development of endometriosis. Further, curcumin inhibited the expression of NF-kappa B, a master regulator of inflammation. Another study in vitro showed that curcumin could arrest endometriotic cells proliferation in a dose-dependent manner by repressing the activity of matrix metalloproteinase-9 (MMP-9), a factor involved in tissue remodeling.

Curcumin could be used as a new line of therapeutic intervention to improve the ovarian function and counteract endometriosis development.

The Clinical Effects

Although our product is a nutritional product, and therefore not regulated by the Food and Drug Administration we need to acknowledge that the ingredients that we have been recommending for years in our practice can be as powerful as prescribed medications if used in the right dosages.

Mitochondrial Enhancer

The mitochondria are intracellular organelles that play a key role in role in egg development, and division and maturation of embryos. Mitochondrial activity is so important that recent studies have revealed that even in embryos that were tested to be genetically normal, mitochondrial defects can lead to poor embryo “behavior” (faulty division) leading to early losses or failed implantation. CoQ10 and Resveratrol are probably the most potent mitochondrial enhancers available. In fact, there are no current pharmacologic interventions regarded to be more powerful than these nutritional supplements to enhance mitochondrial activity.

Anti Inflammatory

Chronic Inflammation lead to scar tissue, pain, infertility and miscarriage. Indeed, control of the inflammatory process is one of the mainstay of the treatment of endometriosis. Usually anti-inflammatories such as ibuprofen (Motrin) are used. But such drugs have remarkable side effects and they can also interfere with ovulation and fertility.

Melatonin, Resveratrol, Curcumin and Pine Tree Bark (Pycnogenol) are clinically proven powerful anti-inflammatory agents. Furthermore they can be taken long term with less side effects.


Endometriosis is often, but not always associated with pain. The pain can be severe and incapacitating. Pain control for endometriosis is very difficult as narcotics like Percocet or Vicodin work only short term and higher doses are required over time due to tolerance. Regular anti-inflammatory drugs like Motrin or Aleve, are somewhat effective but long term use may lead to gastro intestinal problems and interfere with ovulation and fertility. Melatonin has natural analgesic properties and also helps with sleep. French pine tree bark has been shown to be effective with menstrual cramping, Resveratrol may have central analgesic effects.

Aromatase Inhibition

Endometriosis is the presence of endometrial tissue outside the uterus. As is the case with normal endometrium, endometriosis also grows in presence of estrogen. Aromatase is an estrogen producing enzyme that is aberrantly expressed in endometriotic lesions. Aromatase is not expressed in normal endometrium. Resveratrol and Melatonin have shown to be a significant aromatase inhibitor in clinical trials.

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.


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