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ARA 290

Author: Dr. George Shanlikian, M.D.  |   Last Updated: January 29th, 2024

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Potential Benefits of ARA 290

  • Promotes tissue repair [1-18]
  • Relieves neuropathic pain [9, 14, 19-35]
  • Fights diabetes [11, 15, 36-43]
  • Boosts immune function [44-54]

What is ARA 290?

ARA 290, also known as cibinetide, is an 11–amino acid peptide that has potent tissue-protective and tissue-regenerative properties. It is called “nonhematopoietic peptide” because ARA 290 exerts its beneficial effects without stimulating erythropoesis or red blood cell production. Preclinical and clinical studies have shown that by selectively interacting with the innate repair receptor, ARA 290 mediates tissue protection.

How ARA 290 Works

ARA 290 is designed from the structure of erythropoietin. It mediates tissue protection by selectively interacting with the innate repair receptor. This in turn stimulates tissue repair and decreases inflammation and apoptosis (programmed cell death).

ARA-290

Chemical Structure of ARA 290

Research on ARA 290

Promotes Tissue Repair

By selectively interacting with the innate repair receptor, ARA 290 exerts its regenerative effects on different body tissues. Strong scientific evidence supports its benefits on various forms of tissue injuries:

  1. In animal models of kidney injury associated with lack of blood (ischemia), the intravenous injection of ARA 290 improved kidney function and reduced structural damage. [1-2]
  2. In mice with deep partial-thickness cutaneous burn injury, ARA 290 mitigated the innate inflammatory response and decreased the burn depth area. [3]
  3. In mice, ARA 290 administration protected against rhabdomyolysis-induced acute kidney injury. [4]
  4. A 2018 mice study published in the Journal of Cellular and Molecular Medicine also found that ARA 290 prevents programmed cell death (apoptosis) of kidney cells. [5]
  5. In a rat model of inflammatory pain, ARA 290 induced regeneration of nerve fibers. [6]
  6. In mice, ARA 290 protected islets of the pancreas from cytokine-induced damage and apoptosis. [7]
  7. In rats, ARA 290 protected against early renal allograft injury (tissue damage associated with a kidney transplant) by reducing macrophage infiltration. [8]
  8. In patients with sarcoidosis-associated small nerve fiber loss, ARA 290 stimulated eye tissue repair by increasing corneal nerve fiber density. [9]
  9. A 2009 study published in the Journal of Molecular Medicine found that nonerythropoietic tissue protective compounds such as ARA 290 are highly effective facilitators of wound healing. [10]
  10. In rats with spinal cord injury, ARA 290 treatment resulted in increased activity of the cells of the spinal cord. [11]
  11. In rats with nerve inflammation, ARA 290 treatment suppressed inflammation and exhibited tissue protection. [12]
  12. In mouse cells, ARA 290 restored tissue homeostasis by modulating pro-inflammatory signaling pathways. [13]
  13. In a model of retinal ischemia (insufficient blood flow to the eye), ARA 290 prolonged cell survival and enhanced repair of blood vessels. [14]
  14. A cell study found that ARA 290 stimulated the survival and repair of cells involved in blood vessel regeneration. [15]
  15. In mice, ARA 290 suppressed the production of inflammatory cytokines, thus, prolonging the survival of transplanted islet cells. [16]
  16. A study reported that ARA 290 can help speed up wound healing by reducing inflammation and cell death. [17]
  17. In mice with diabetic wounds, daily injections with ARA 290 improved angiogenesis (formation of new blood vessels), scar strength, and time to complete wound closure. [18]

Relieves Neuropathic Pain

Neuropathic pain is often debilitating because it presents as a shooting or burning pain. Sometimes, it can resolve on its own but is usually chronic in nature. In worst cases, it comes and goes and can significantly alter one’s quality of life. Interestingly, there is an overwhelming body of clinical evidence suggesting that ARA 290 can offer long-term relief for neuropathic pain associated with nerve damage or a malfunctioning nervous system:

  1. A 2016 study published in the Peptides journal found that ARA 290-mediated analgesic effect is achieved by blocking or influencing receptors in pain sensation. [14]
  2. In mice, ARA 290 relieved capsaicin-induced mechanical allodynia by inhibiting capsaicin-evoked TRPV1 channel activity, a modulator of nerve inflammation and pain sensation. [19]
  3. In patients with type 2 diabetes who are suffering from neuropathic symptoms, ARA 290 showed significant potential for the treatment of diabetic small fiber neuropathy. [20]
  4. In patients with neuropathic pain related to sarcoidosis, an inflammatory disease affecting multiple body organs, ARA 290 significantly reduced pain and improved quality of life. [9, 21-25]
  5. A 2016 study published in the Pain Reports journal found that ARA 290 treats neuropathic pain by effectively reprogramming the pro-inflammatory and tissue-damaging process into healing and tissue repair. [26]
  6. In a rat neuritis (nerve inflammation) model, ARA 290 prevented the development of mechanical allodynia (increased pain sensitivity to non-painful stimuli). [27]
  7. In a mouse model of diabetic neuropathy, ARA 290 induced repair of small autonomic nerve fibers within the sympathetic ganglia (nerve cell bodies along the spinal cord). [28]
  8. In mice with pain associated with sciatic nerve injury, ARA 290 prevented the development of mechanical allodynia. [29]
  9. In rats, weekly injections with ARA290 produced long-term relief of neuropathic pain. [30]
  10. In mice with spinal cord injury, ARA 290 reduced neuropathic pain by suppressing spinal inflammatory mediators such as CCL2. [31]
  11. In a murine model, ARA 290 reduced neuropathic pain by reducing the levels of the inflammatory substance TNF-α. [32]
  12. Studies found that ARA 290 relieved neuropathic pain in patients with sarcoidosis by improving corneal nerve fiber abundance. [33-34]
  13. In rats and mice with peripheral nerve injury, ARA 290 produced significant relief of allodynia. [35]

Fights Diabetes

Evidence also suggests that ARA290 possesses potent anti-diabetic properties that can be beneficial in patients with diabetes mellitus and chronically elevated blood sugar levels:

  1. In animal models of diabetic neuropathy, ARA 290 improved blood sugar levels by reducing the underlying inflammation. [11]
  2. In patients with type 2 diabetes, ARA 290 administration at a dose of 4 mg daily for 28 days resulted in a significant improvement in hemoglobin A1c. [15]
  3. In diabetic patients, ARA 290 administration restored glucose homeostasis (blood sugar balance). [36]
  4. A study found that ARA 290 promotes glucose homeostasis by targeting the innate repair receptor. [37]
  5. In individuals with prediabetes and/or drug-naive type 2 diabetes, ARA 290 administration resulted in improved glucose tolerance, insulin secretion, insulin sensitivity, and long-term glucose control. [38]
  6. In type 2 diabetic Goto-Kakizaki (GK) rats, oral administration of ARA 290 for 4 weeks improved β-cell glucose metabolism and [Ca(2+)]i handling, resulting in enhanced insulin release. [39-40]
  7. In a murine model of diabetes, ARA 290 reversed diabetes-induced autonomic nerve degeneration. [41]
  8. In patients with prediabetes and type 2 diabetes, ARA 290 treatment for 2-4 weeks improved oral glucose tolerance tests and insulin secretion. [42]
  9. In rats, ARA 290 protected pancreatic islets (secrete insulin) from cytokine-induced damage and programmed cell death (apoptosis). [43]

Boosts Immune Function

A growing body of evidence suggests that ARA 290 also has immune-modulating properties necessary for warding off a wide array of diseases:

  1. In a cell culture model, ARA 290 modulated the innate immune response and reduced invasion of the bacterium Escherichia coli. [44]
  2. Several studies also found that ARA 290 and other nonhematopoietic peptides have the potential to combat several inflammatory and infectious diseases. [45-47]
  3. A 2017 study published in Scientific Reports found that ARA 290 enhances immune cell function through its potent anti-inflammatory effects. [48]
  4. A 2016 study found that ARA 290 improves stem cells’ ability to find their destination (homing), thus, enhancing new blood vessel formation, tissue regeneration, and immune function. [49]
  5. A 2014 study published in the Journal of Immunology found that ARA 290 alters T cell function to suppress inflammation. [50]
  6. A study found that ARA 290 can help lower the risk of myocardial infarction by protecting against damage to the heart muscle (myocardium). [51]
  7. A study reported that ARA 290 has the ability to modulate graft rejection after organ transplant. [52]
  8. Studies found that the anti-inflammatory effects of ARA 290 can help treat autoimmune diseases such as Crohn’s disease, ulcerative colitis, and systemic lupus erythematosus (SLE). [53-54]

Associated Side Effects of ARA 290

ARA 290 side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on ARA 290. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of ARA 290. Despite this, it was listed as a side effect associated with ARA 290 even though these associated side effects are very uncommon.
Side effects associated with ARA 290 may include the following:

  • Elevated blood pressure
  • Fast heart rate
  • Liver enzyme elevation
  • Nausea/vomiting
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Reference

  1. Van rijt WG, Nieuwenhuijs-moeke GJ, Van goor H, et al. ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury. J Transl Med. 2013;11:9.

  2. Van rijt WG, Nieuwenhuijs-moeke GJ, Van goor H, Ottens PJ, Ploeg RJ, Leuvenink HG. Renoprotective capacities of non-erythropoietic EPO derivative, ARA290, following renal ischemia/reperfusion injury. J Transl Med. 2013;11:286.

  3. Bohr S, Patel SJ, Shen K, et al. Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns. ProcNatlAcadSci USA. 2013;110(9):3513-8.

  4. Retrieved https://www.nature.com/articles/cddis2017104

  5. Huang B, Jiang J, Luo B, et al. Non-erythropoietic erythropoietin-derived peptide protects mice from systemic lupus erythematosus. J Cell Mol Med. 2018;22(7):3330-3339.

  6. Dilley A. ARA290 in a rat model of inflammatory pain. Methods Mol Biol. 2013;982:213-25.

  7. Watanabe M, Lundgren T, Saito Y, et al. A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets. Transplantation. 2016;100(3):554-62.

  8. Yan L, Zhang H, Gao S, et al. EPO Derivative ARA290 Attenuates Early Renal Allograft Injury in Rats by Targeting NF-κB Pathway. Transplant Proc. 2018;50(5):1575-1582.

  9. Dahan A, Dunne A, Swartjes M, Proto PL, Heij L, Vogels O, van Velzen M, Sarton E, Niesters M, Tannemaat MR, Cerami A, Brines M. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med 2013;19:334–45.

  10. Erbayraktar Z, Erbayraktar S, Yilmaz O, Cerami A, Coleman T, Brines M. Nonerythropoietic tissue protective compounds are highly effective facilitators of wound healing. Mol Med. 2009;15(7-8):235–241. doi:10.2119/molmed.2009.00051.

  11. Swartjes M, van Velzen M, Niesters M, Aarts L, Brines M, Dunne A, Cerami A, Dahan A. ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain 2014;10:13.

  12. Liu Y, Luo B, Han F, et al. Erythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection [published correction appears in PLoS One. 2014;9(5):e99555. Dosage error in article text]. PLoS One. 2014;9(3):e90942. Published 2014 Mar 6. doi:10.1371/journal.pone.0090942.

  13. Bohr S, Patel SJ, Vasko R, et al. Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells. J Mol Med (Berl). 2015;93(2):199–210. doi:10.1007/s00109-014-1218-2.

  14. O’Leary, O. E., Canning, P., Reid, E., Bertelli, P. M., McKeown, S., Brines, M., Cerami, A., Du, X., Xu, H., Chen, M., Dutton, L., Brazil, D. P., Medina, R. J., & Stitt, A. W. (2019). The vasoreparative potential of endothelial colony-forming cells in the ischemic retina is enhanced by cibinetide, a non-hematopoietic erythropoietin mimetic. Experimental eye research, 182, 144–155. https://doi.org/10.1016/j.exer.2019.03.001.

  15. Hache, G., Garrigue, P., Bennis, Y., Stalin, J., Moyon, A., Cerami, A., Brines, M., Blot-Chabaud, M., Sabatier, F., Dignat-George, F., & Guillet, B. (2016). ARA290, a Specific Agonist of Erythropoietin/CD131 Heteroreceptor, Improves Circulating Endothelial Progenitors’ Angiogenic Potential and Homing Ability. Shock (Augusta, Ga.), 46(4), 390–397. https://doi.org/10.1097/SHK.0000000000000606.

  16. Watanabe, M., Lundgren, T., Saito, Y., Cerami, A., Brines, M., Östenson, C. G., & Kumagai-Braesch, M. (2016). A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets. Transplantation, 100(3), 554–562. https://doi.org/10.1097/TP.0000000000001026

  17. Peng B, Kong G, Yang C, Ming Y. Erythropoietin and its derivatives: from tissue protection to immune regulation. Cell Death Dis. 2020 Feb 3;11(2):79. doi: 10.1038/s41419-020-2276-8. PMID: 32015330; PMCID: PMC6997384.

  18. Bitto, A., Irrera, N., Pizzino, G., Pallio, G., Mannino, F., Vaccaro, M., Arcoraci, V., Aliquò, F., Minutoli, L., Colonna, M. R., Galeano, M. R., Brines, M., De Ponte, C., Collino, M., Squadrito, F., & Altavilla, D. (2018). Activation of the EPOR-β common receptor complex by cibinetide ameliorates impaired wound healing in mice with genetic diabetes. Biochimica et biophysica acta. Molecular basis of disease, 1864(2), 632–639. https://doi.org/10.1016/j.bbadis.2017.12.006.

  19. Zhang W, Yu G, Zhang M. ARA 290 relieves pathophysiological pain by targeting TRPV1 channel: Integration between immune system and nociception. Peptides. 2016;76:73-9.

  20. Heij L, Niesters M, Swartjes M, et al. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med. 2012;18:1430-6.

  21. Brines M, Dunne AN, Van velzen M, et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015;20:658-66.

  22. Available from https://www.tandfonline.com/doi/full/10.1517/21678707.2013.719289.

  23. Niesters M, Swartjes M, Heij L, Brines M, Cerami A, Dunne A, Hoitsma E, Dahan A. The erythropoietin analog ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain. Expert Opin Orphan Drugs 2013;1:77–87.

  24. van Velzen M, Heij L, Niesters M, Cerami A, Dunne A, Dahan A, Brines M. ARA 290 for treatment of small fiber neuropathy in sarcoidosis. Expert OpinInvestig Drugs 2014;23:541–50.

  25. Dahan A, Brines M, Niesters M, Cerami A, van Velzen M. Targeting the innate repair receptor to treat neuropathy. Pain Rep. 2016;1(1):e566. Published 2016 Aug 9. doi:10.1097/PR9.0000000000000566.

  26. Pulman KG, Smith M, Mengozzi M, Ghezzi P, Dilley A. The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model. Neuroscience 2013;233:174–83.

  27. Schmidt RE, Feng D, Wang Q, Green KG, Snipes LL, Yamin M, Brines M. Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuriticdystrophy and neuronopathy in Akita (Ins2 Akita) diabetic mouse sympathetic ganglia. ExpNeurol 2011;232:126–35.

  28. Swartjes M, Morariu A, Niesters M, Brines M, Cerami A, Aarts L, Dahan A. ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and beta-common receptor knockout mice. Anesthesiology 2011;115:1084–92.

  29. Swartjes M, Niesters M, Heij L, Dunne A, Aarts L, Hand CC, Kim HS, Brines M, Cerami A, Dahan A. Ketamine does not produce relief of neuropathic pain in mice lacking the beta-common receptor (CD131). PLoS One 2013;8:e71326.

  30. Takahashi T, Kinoshita M, Shono S, Habu Y, Ogura T, Seki S, Kazama T. The effect of ketamine anesthesia on the immune function of mice with postoperative septicemia. Anesth Analgesia 2010;111:1051–8.

  31. Culver DA, Dahan A, Bajorunas D, et al. Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Invest Ophthalmol Vis Sci. 2017;58(6):BIO52-BIO60.

  32. Retrieved from https://clinicaltrials.gov/ct2/show/NCT02039687.

  33. Swartjes, M., Morariu, A., Niesters, M., Brines, M., Cerami, A., Aarts, L., & Dahan, A. (2011). ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and β-common receptor knockout mice. Anesthesiology, 115(5), 1084–1092. https://doi.org/10.1097/ALN.0b013e31822fcefd.

  34. Retrieved from https://pdfs.semanticscholar.org/7d4b/9ec022053c196726a65c4fe1732736d6aa48.pdf

  35. Retrieved from https://doloranimal.org/images/fdocum/targeting_the_innate_repair_receptor_to_treat.2.pdf

  36. Retrieved from https://ichgcp.net/clinical-trials-registry/NCT01933529

  37. Muller C, Yassin K, Li LS, et al. ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats. Mol Med. 2016;21(1):969–978. doi:10.2119/molmed.2015.00267.

  38. Muller C, et al. (2013) Thenonhematopoietic erythropoietin analogue ARA 290 improves glucose tolerance by stimulating insulin secretion in spontaneously type 2 diabetic Goto-Kakizaki rats. Diabetologia. 56(Suppl 1):S268.

  39. Schmidt RE, et al. Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2 Akita) diabetic mouse sympathetic ganglia. Exp Neurol. 2011;232:126–35.

  40. Retrieved from https://clinicaltrials.gov/ct2/show/NCT01933529

  41. Available from https://www.researchgate.net/publication/310146980_An_Engineered_Innate_Repair_Receptor_Agonist_ARA_290_Protects_Rat_Islets_from_Cytokine-induced_Apoptosis.

  42. Polgárová K, Lüthje P, Cerami A, Brauner A. The erythropoietin analogue ARA290 modulates the innate immune response and reduces Escherichia coli invasion into urothelial cells. FEMS Immunol Med Microbiol. 2011;62(2):190-6.

  43. Macdougall I.C., Rossert J., Casadevall N., Stead R.B., Duliege A.M., Froissart M., Eckardt K.U. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N. Engl. J. Med. 2009;361:1848–1855.

  44. Wrighton N.C., Farrell F.X., Chang R., Kashyap A.K., Barbone F.P., Mulcahy L.S., Johnson D.L., Barrett R.W., Jolliffe L.K., Dower W.J. Small peptides as potent mimetics of the protein hormone erythropoietin. Science. 1996;273:458–464.

  45. Brines M., Patel N.S., Villa P., Brines C., Mennini T., De Paola M., Erbayraktar Z., Erbayraktar S., Sepodes B., Thiemermann C., Ghezzi P., Yamin M., Hand C.C., Xie Q.W., Coleman T., Cerami A. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc. Natl. Acad. Sci. U S A. 2008;105:10925–10930.

  46. Nairz M, Haschka D, Dichtl S, et al. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Sci Rep. 2017;7(1):13012.

  47. Hache G, Garrigue P, Bennis Y, et al. ARA290, a Specific Agonist of Erythropoietin/CD131 Heteroreceptor, Improves Circulating Endothelial Progenitors’ Angiogenic Potential and Homing Ability. Shock. 2016;46(4):390-7.

  48. Chen H, Luo B, Yang X, et al. Therapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat. J Neuroimmunol. 2014;268(1-2):64-70.

  49. Ahmet I, et al. A small nonerythropoietic helix B surface peptide based upon erythropoietin structure is cardioprotective against ischemic myocardial damage. Mol Med. 2011;17:194–200.

  50. Yan, L., Zhang, H., Gao, S., Zhu, G., Zhu, Q., Gu, Y., & Shao, F. (2018). EPO Derivative ARA290 Attenuates Early Renal Allograft Injury in Rats by Targeting NF-κB Pathway. Transplantation proceedings, 50(5), 1575–1582. https://doi.org/10.1016/j.transproceed.2018.03.015.

  51. Nairz, M., Haschka, D., Dichtl, S., Sonnweber, T., Schroll, A., Aßhoff, M., Mindur, J. E., Moser, P. L., Wolf, D., Swirski, F. K., Theurl, I., Cerami, A., Brines, M., & Weiss, G. (2017). Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Scientific reports, 7(1), 13012. https://doi.org/10.1038/s41598-017-13046-3.

  52. Huang, B., Jiang, J., Luo, B., Zhu, W., Liu, Y., Wang, Z., & Zhang, Z. (2018). Non-erythropoietic erythropoietin-derived peptide protects mice from systemic lupus erythematosus. Journal of cellular and molecular medicine, 22(7), 3330–3339. https://doi.org/10.1111/jcmm.13608.

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